Academic Appointments


Honors & Awards


  • Gabilan Fellow Award, Stanford University (2019)
  • Chambers Fellow Award, Dudley Chambers, Stanford University (2018-2021)
  • Terman Fellow Award, Hewlett Foundation, Stanford University (2010-2013)
  • Kimmel Scholar Award, Sidney Kimmel Foundation for Cancer Research (2010-2012)
  • Pathways to Independence Award (K99/R00), NIH (2009-2012)

Professional Education


  • Postdoctoral Fellow, MD Anderson Cancer Center, Carcinogenesis (2009)
  • Ph.D., Baylor College of Medicine, Biomedical Sciences (2004)

Patents


  • Solomon Endlich, Devin King, Ashby J Morrison. "United States Patent 11,155,806 Methods and Uses of Introducing Mutations into Genetic Material for Genome Assembly", The Board of Trustees of the Leland Stanford Junior University, Oct 26, 2021

Current Research and Scholarly Interests


Our research interests are to elucidate the contribution of chromatin to mechanisms that promote genomic integrity. The regulation of chromatin is a crucial component of DNA metabolism and processing in eukaryotic organisms. Chromatin-remodeling complexes, modified histones, and higher order chromatin structure are all factors influencing genome stability. We utilize an integrated approach of genetic, biochemical, and molecular techniques, in both yeast and mammalian systems, to examine the involvement of chromatin in processes that prevent genome instability and the pathogenesis of disease.

Stanford Advisees


Graduate and Fellowship Programs


All Publications


  • Retinoblastoma protein regulates carcinogen susceptibility at heterochromatic cancer driver loci. Life science alliance Wong, K. M., King, D. A., Schwartz, E. K., Herrera, R. E., Morrison, A. J. 1800; 5 (4)

    Abstract

    Carcinogenic insult, such as UV light exposure, creates DNA lesions that evolve into mutations if left unrepaired. These resulting mutations can contribute to carcinogenesis and drive malignant phenotypes. Susceptibility to carcinogens (i.e., the propensity to form a carcinogen-induced DNA lesion) is regulated by both genetic and epigenetic factors. Importantly, carcinogen susceptibility is a critical contributor to cancer mutagenesis. It is known that mutations can be prevented by tumor suppressor regulation of DNA damage response pathways; however, their roles carcinogen susceptibility have not yet been reported. In this study, we reveal that the retinoblastoma (RB1) tumor suppressor regulates UV susceptibility across broad regions of the genome. In particular, centromere and telomere-proximal regions exhibit significant increases in UV lesion susceptibility when RB1 is deleted. Several cancer-related genes are located within genomic regions of increased susceptibility, including telomerase reverse transcriptase, TERT, thereby accelerating mutagenic potential in cancers with RB1 pathway alterations. These findings reveal novel genome stability mechanisms of a tumor suppressor and uncover new pathways to accumulate mutations during cancer evolution.

    View details for DOI 10.26508/lsa.202101134

    View details for PubMedID 34983823

  • Endocardial/endothelial angiocrines regulate cardiomyocyte development and maturation and induce features of ventricular non-compaction. European heart journal Rhee, S., Paik, D. T., Yang, J. Y., Nagelberg, D., Williams, I., Tian, L., Roth, R., Chandy, M., Ban, J., Belbachir, N., Kim, S., Zhang, H., Phansalkar, R., Wong, K. M., King, D. A., Valdez, C., Winn, V. D., Morrison, A. J., Wu, J. C., Red-Horse, K. 2021

    Abstract

    AIMS: Non-compaction cardiomyopathy is a devastating genetic disease caused by insufficient consolidation of ventricular wall muscle that can result in inadequate cardiac performance. Despite being the third most common cardiomyopathy, the mechanisms underlying the disease, including the cell types involved, are poorly understood. We have previously shown that endothelial cell-specific deletion of the chromatin remodeller gene Ino80 results in defective coronary vessel development that leads to ventricular non-compaction in embryonic mouse hearts. We aimed to identify candidate angiocrines expressed by endocardial and ECs inwildtype and LVNC conditions in Tie2Cre;Ino80fl/fl transgenic embryonic mouse hearts, and test the effect of these candidates on cardiomyocyte proliferation and maturation.METHODS AND RESULTS: We used single-cell RNA-sequencing to characterize endothelial and endocardial defects in Ino80-deficient hearts. We observed a pathological endocardial cell population in the non-compacted hearts and identified multiple dysregulated angiocrine factors that dramatically affected cardiomyocyte behaviour. We identified Col15A1 as a coronary vessel-secreted angiocrine factor, downregulated by Ino80-deficiency, that functioned to promote cardiomyocyte proliferation. Furthermore, mutant endocardial and endothelial cells (ECs) up-regulated expression of secreted factors, such as Tgfbi, Igfbp3, Isg15, and Adm, which decreased cardiomyocyte proliferation and increased maturation.CONCLUSIONS: These findings support a model where coronary ECs normally promote myocardial compaction through secreted factors, but that endocardial and ECs can secrete factors that contribute to non-compaction under pathological conditions.

    View details for DOI 10.1093/eurheartj/ehab298

    View details for PubMedID 34279605

  • Genome-wide profiles of UV lesion susceptibility, repair, and mutagenic potential in melanoma. Mutation research Perez, B. S., Wong, K. M., Schwartz, E. K., Herrera, R. E., King, D. A., Garcia-Nieto, P. E., Morrison, A. J. 2021; 823: 111758

    Abstract

    Exposure to the ultraviolet (UV) radiation in sunlight creates DNA lesions, which if left unrepaired can induce mutations and contribute to skin cancer. The two most common UV-induced DNA lesions are the cis-syn cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs), both of which can initiate mutations. Interestingly, mutation frequency across the genomes of many cancers is heterogenous with significant increases in heterochromatin. Corresponding increases in UV lesion susceptibility and decreases in repair are observed in heterochromatin versus euchromatin. However, the individual contributions of CPDs and 6-4PPs to mutagenesis have not been systematically examined in specific genomic and epigenomic contexts. In this study, we compared genome-wide maps of 6-4PP and CPD lesion abundances in primary cells and conducted comprehensive analyses to determine the genetic and epigenetic features associated with susceptibility. Overall, we found a high degree of similarity between 6-4PP and CPD formation, with an enrichment of both in heterochromatin regions. However, when examining the relative levels of the two UV lesions, we found that bivalent and Polycomb-repressed chromatin states were uniquely more susceptible to 6-4PPs. Interestingly, when comparing UV susceptibility and repair with melanoma mutation frequency in these regions, disparate patterns were observed in that susceptibility was not always inversely associated with repair and mutation frequency. Functional enrichment analysis hint at mechanisms of negative selection for these regions that are essential for cell viability, immune function and induce cell death when mutated. Ultimately, these results reveal both the similarities and differences between UV-induced lesions that contribute to melanoma.

    View details for DOI 10.1016/j.mrfmmm.2021.111758

    View details for PubMedID 34333390

  • Cancer Cell Metabolism Connects Epigenetic Modifications to Transcriptional Regulation. The FEBS journal Morrison, A. J. 2021

    Abstract

    Adaptation of cellular function with the nutrient environment is essential for survival. Failure to adapt can lead to cell death and/or disease. Indeed, energy metabolism alterations are a major contributing factor for many pathologies, including cancer, cardiovascular disease, and diabetes. In particular, a primary characteristic of cancer cells is altered metabolism that promotes survival and proliferation even in the presence of limited nutrients. Interestingly, recent studies demonstrate that metabolic pathways produce intermediary metabolites that directly influence epigenetic modifications in the genome. Emerging evidence demonstrates that metabolic processes in cancer cells fuel malignant growth, in part, through epigenetic regulation of gene expression programs important for proliferation and adaptive survival. In this review, recent progress towards understanding the relationship of cancer cell metabolism, epigenetic modification, and transcriptional regulation will be discussed. Specifically, the need for adaptive cell metabolism and its modulation in cancer cells will be introduced. Current knowledge on the emerging field of metabolite production and epigenetic modification will also be reviewed. Alterations of DNA (de)methylation, histone modifications, such as (de)methylation and (de)acylation, as well as chromatin remodeling, will be discussed in the context of cancer cell metabolism. Finally, how these epigenetic alterations contribute to cancer cell phenotypes will summarized. Collectively, these studies reveal that both metabolic and epigenetic pathways in cancer cells are closely linked, representing multiple opportunities to therapeutically target the unique features of malignant growth.

    View details for DOI 10.1111/febs.16032

    View details for PubMedID 34036737

  • Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure. Nature genetics Akdemir, K. C., Le, V. T., Kim, J. M., Killcoyne, S., King, D. A., Lin, Y., Tian, Y., Inoue, A., Amin, S. B., Robinson, F. S., Nimmakayalu, M., Herrera, R. E., Lynn, E. J., Chan, K., Seth, S., Klimczak, L. J., Gerstung, M., Gordenin, D. A., O'Brien, J., Li, L., Deribe, Y. L., Verhaak, R. G., Campbell, P. J., Fitzgerald, R., Morrison, A. J., Dixon, J. R., Andrew Futreal, P. 2020

    Abstract

    Somatic mutations in driver genes may ultimately lead to the development of cancer. Understanding how somatic mutations accumulate in cancer genomes and the underlying factors that generate somatic mutations is therefore crucial for developing novel therapeutic strategies. To understand the interplay between spatial genome organization and specific mutational processes, we studied 3,000 tumor-normal-pair whole-genome datasets from 42 different human cancer types. Our analyses reveal that the change in somatic mutational load in cancer genomes is co-localized with topologically-associating-domain boundaries. Domain boundaries constitute a better proxy to track mutational load change than replication timing measurements. We show that different mutational processes lead to distinct somatic mutation distributions where certain processes generate mutations in active domains, and others generate mutations in inactive domains. Overall, the interplay between three-dimensional genome organization and active mutational processes has a substantial influence on the large-scale mutation-rate variations observed in human cancers.

    View details for DOI 10.1038/s41588-020-0708-0

    View details for PubMedID 33020667

  • Chromatin-remodeling links metabolic signaling to gene expression. Molecular metabolism Morrison, A. J. 2020: 100973

    Abstract

    BACKGROUND: ATP-dependent chromatin remodelers are evolutionarily conserved complexes that alter nucleosome positioning to influence many DNA-templated processes, such as replication, repair, and transcription. In particular, chromatin remodeling can dynamically regulate gene expression by altering accessibility of chromatin to transcription factors.SCOPE OF REVIEW: This review provides an overview of the importance of chromatin remodelers in the regulation of metabolic gene expression. Particular emphasis is placed on the INO80 and SWI/SNF (BAF/PBAF) chromatin remodelers in both yeast and mammals. This review details discoveries from the initial identification of chromatin remodelers in Saccharomyces cerevisiae to recent discoveries in the metabolic requirements of developing embryonic tissues in mammals.MAJOR CONCLUSIONS: INO80 and SWI/SNF (BAF/PBAF) chromatin remodelers regulate the expression of energy metabolism pathways in S.cerevisiae and mammals in response to diverse nutrient environments. In particular, the INO80 complex organizes the temporal expression of gene expression in the metabolically synchronized S.cerevisiae system. INO80-mediated chromatin remodeling is also needed to constrain cell division during metabolically favorable conditions. Conversely, the BAF/PBAF remodeler regulates tissue-specific glycolytic metabolism and is disrupted in cancers that are dependent on glycolysis for proliferation. The role of chromatin remodeling in metabolic gene expression is downstream of the metabolic signaling pathways, such as the TOR pathway, a critical regulator of metabolic homeostasis. Furthermore, the INO80 and BAF/PBAF chromatin remodelers have both been shown to regulate heart development, the tissues of which have unique requirements for energy metabolism during development. Collectively, these results demonstrate that chromatin remodelers communicate metabolic status to chromatin and are a central component of homeostasis pathways that optimize cell fitness, organismal development, and prevent disease.

    View details for DOI 10.1016/j.molmet.2020.100973

    View details for PubMedID 32251664

  • The somatic mutation landscape of the human body. Genome biology Garcia-Nieto, P. E., Morrison, A. J., Fraser, H. B. 2019; 20 (1): 298

    Abstract

    BACKGROUND: Somatic mutations in healthy tissues contribute to aging, neurodegeneration, and cancer initiation, yet they remain largely uncharacterized.RESULTS: To gain a better understanding of the genome-wide distribution and functional impact of somatic mutations, we leverage the genomic information contained in the transcriptome to uniformly call somatic mutations from over 7500 tissue samples, representing 36 distinct tissues. This catalog, containing over 280,000 mutations, reveals a wide diversity of tissue-specific mutation profiles associated with gene expression levels and chromatin states. For example, lung samples with low expression of the mismatch-repair gene MLH1 show a mutation signature of deficient mismatch repair. In addition, we find pervasive negative selection acting on missense and nonsense mutations, except for mutations previously observed in cancer samples, which are under positive selection and are highly enriched in many healthy tissues.CONCLUSIONS: These findings reveal fundamental patterns of tissue-specific somatic evolution and shed light on aging and the earliest stages of tumorigenesis.

    View details for DOI 10.1186/s13059-019-1919-5

    View details for PubMedID 31874648

  • Recognition of Histone Crotonylation by Taf14 Links Metabolic State to Gene Expression. Molecular cell Gowans, G. J., Bridgers, J. B., Zhang, J., Dronamraju, R., Burnetti, A., King, D. A., Thiengmany, A. V., Shinsky, S. A., Bhanu, N. V., Garcia, B. A., Buchler, N. E., Strahl, B. D., Morrison, A. J. 2019

    Abstract

    Metabolic signaling to chromatin often underlies how adaptive transcriptional responses are controlled. While intermediary metabolites serve as co-factors for histone-modifying enzymes during metabolic flux, how these modifications contribute to transcriptional responses is poorly understood. Here, we utilize the highly synchronized yeast metabolic cycle (YMC) and find that fatty acid beta-oxidation genes are periodically expressed coincident with the beta-oxidation byproduct histone crotonylation. Specifically, we found that H3K9 crotonylation peaks when H3K9 acetylation declines and energy resources become limited. During this metabolic state, pro-growth gene expression is dampened; however, mutation of the Taf14 YEATS domain, a H3K9 crotonylation reader, results in de-repression of these genes. Conversely, exogenous addition of crotonic acid results in increased histone crotonylation, constitutive repression of pro-growth genes, and disrupted YMC oscillations. Together, our findings expose an unexpected link between metabolic flux and transcription and demonstrate that histone crotonylation and Taf14 participate in the repression of energy-demanding gene expression.

    View details for DOI 10.1016/j.molcel.2019.09.029

    View details for PubMedID 31676231

  • The Yeast INO80 Complex Operates as a Tunable DNA Length-Sensitive Switch to Regulate Nucleosome Sliding. Molecular cell Zhou, C. Y., Johnson, S. L., Lee, L. J., Longhurst, A. D., Beckwith, S. L., Johnson, M. J., Morrison, A. J., Narlikar, G. J. 2018; 69 (4): 677-688.e9

    Abstract

    The yeast INO80 chromatin remodeling complex plays essential roles in regulating DNA damage repair, replication, and promoter architecture. INO80's role in these processes is likely related to its ability to slide nucleosomes, but the underlying mechanism is poorly understood. Here we use ensemble and single-molecule enzymology to study INO80-catalyzed nucleosome sliding. We find that the rate of nucleosome sliding by INO80 increases ∼100-fold when the flanking DNA length is increased from 40 to 60 bp. Furthermore, once sliding is initiated, INO80 moves the nucleosome rapidly at least 20 bp without pausing to re-assess flanking DNA length, and it can change the direction of nucleosome sliding without dissociation. Finally, we show that the Nhp10 module of INO80 plays an auto-inhibitory role, tuning INO80's switch-like response to flanking DNA. Our results indicate that INO80 is a highly processive remodeling motor that is tightly regulated by both substrate cues and non-catalytic subunits.

    View details for DOI 10.1016/j.molcel.2018.01.028

    View details for PubMedID 29452642

    View details for PubMedCentralID PMC5897057

  • The INO80 chromatin remodeler sustains metabolic stability by promoting TOR signaling and regulating histone acetylation. PLoS genetics Beckwith, S. L., Schwartz, E. K., García-Nieto, P. E., King, D. A., Gowans, G. J., Wong, K. M., Eckley, T. L., Paraschuk, A. P., Peltan, E. L., Lee, L. R., Yao, W., Morrison, A. J. 2018; 14 (2): e1007216

    Abstract

    Chromatin remodeling complexes are essential for gene expression programs that coordinate cell function with metabolic status. However, how these remodelers are integrated in metabolic stability pathways is not well known. Here, we report an expansive genetic screen with chromatin remodelers and metabolic regulators in Saccharomyces cerevisiae. We found that, unlike the SWR1 remodeler, the INO80 chromatin remodeling complex is composed of multiple distinct functional subunit modules. We identified a strikingly divergent genetic signature for the Ies6 subunit module that links the INO80 complex to metabolic homeostasis. In particular, mitochondrial maintenance is disrupted in ies6 mutants. INO80 is also needed to communicate TORC1-mediated signaling to chromatin, as ino80 mutants exhibit defective transcriptional profiles and altered histone acetylation of TORC1-responsive genes. Furthermore, comparative analysis reveals subunits of INO80 and mTORC1 have high co-occurrence of alterations in human cancers. Collectively, these results demonstrate that the INO80 complex is a central component of metabolic homeostasis that influences histone acetylation and may contribute to disease when disrupted.

    View details for DOI 10.1371/journal.pgen.1007216

    View details for PubMedID 29462149

    View details for PubMedCentralID PMC5834206

  • INO80 Chromatin Remodeling Coordinates Metabolic Homeostasis with Cell Division CELL REPORTS Gowans, G. J., Schep, A. N., Wong, K., King, D. A., Greenleaf, W. J., Morrison, A. J. 2018; 22 (3): 611–23

    Abstract

    Adaptive survival requires the coordination of nutrient availability with expenditure of cellular resources. For example, in nutrient-limited environments, 50% of all S. cerevisiae genes synchronize and exhibit periodic bursts of expression in coordination with respiration and cell division in the yeast metabolic cycle (YMC). Despite the importance of metabolic and proliferative synchrony, the majority of YMC regulators are currently unknown. Here, we demonstrate that the INO80 chromatin-remodeling complex is required to coordinate respiration and cell division with periodic gene expression. Specifically, INO80 mutants have severe defects in oxygen consumption and promiscuous cell division that is no longer coupled with metabolic status. In mutant cells, chromatin accessibility of periodic genes, including TORC1-responsive genes, is relatively static, concomitant with severely attenuated gene expression. Collectively, these results reveal that the INO80 complex mediates metabolic signaling to chromatin to restrict proliferation to metabolically optimal states.

    View details for PubMedID 29346761

  • Endothelial deletion of Ino80 disrupts coronary angiogenesis and causes congenital heart disease. Nature communications Rhee, S. n., Chung, J. I., King, D. A., D'amato, G. n., Paik, D. T., Duan, A. n., Chang, A. n., Nagelberg, D. n., Sharma, B. n., Jeong, Y. n., Diehn, M. n., Wu, J. C., Morrison, A. J., Red-Horse, K. n. 2018; 9 (1): 368

    Abstract

    During development, the formation of a mature, well-functioning heart requires transformation of the ventricular wall from a loose trabecular network into a dense compact myocardium at mid-gestation. Failure to compact is associated in humans with congenital diseases such as left ventricular non-compaction (LVNC). The mechanisms regulating myocardial compaction are however still poorly understood. Here, we show that deletion of the Ino80 chromatin remodeler in vascular endothelial cells prevents ventricular compaction in the developing mouse heart. This correlates with defective coronary vascularization, and specific deletion of Ino80 in the two major coronary progenitor tissues-sinus venosus and endocardium-causes intermediate phenotypes. In vitro, endothelial cells promote myocardial expansion independently of blood flow in an Ino80-dependent manner. Ino80 deletion increases the expression of E2F-activated genes and endothelial cell S-phase occupancy. Thus, Ino80 is essential for coronary angiogenesis and allows coronary vessels to support proper compaction of the heart wall.

    View details for PubMedID 29371594

  • Genome maintenance functions of the INO80 chromatin remodeller PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Morrison, A. J. 2017; 372 (1731)

    Abstract

    Chromatin modification is conserved in all eukaryotes and is required to facilitate and regulate DNA-templated processes. For example, chromatin manipulation, such as histone post-translational modification and nucleosome positioning, play critical roles in genome stability pathways. The INO80 chromatin-remodelling complex, which regulates the abundance and positioning of nucleosomes, is particularly important for proper execution of inducible responses to DNA damage. This review discusses the participation and activity of the INO80 complex in DNA repair and cell cycle checkpoint pathways, with emphasis on the Saccharomyces cerevisiae model system. Furthermore, the role of ATM/ATR kinases, central regulators of DNA damage signalling, in the regulation of INO80 function will be reviewed. In addition, emerging themes of chromatin remodelling in mitotic stability pathways and chromosome segregation will be introduced. These studies are critical to understanding the dynamic chromatin landscape that is rapidly and reversibly modified to maintain the integrity of the genome.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'.

    View details for PubMedID 28847826

    View details for PubMedCentralID PMC5577467

  • Carcinogen susceptibility is regulated by genome architecture and predicts cancer mutagenesis. The EMBO journal García-Nieto, P. E., Schwartz, E. K., King, D. A., Paulsen, J., Collas, P., Herrera, R. E., Morrison, A. J. 2017; 36 (19): 2829-2843

    Abstract

    The development of many sporadic cancers is directly initiated by carcinogen exposure. Carcinogens induce malignancies by creating DNA lesions (i.e., adducts) that can result in mutations if left unrepaired. Despite this knowledge, there has been remarkably little investigation into the regulation of susceptibility to acquire DNA lesions. In this study, we present the first quantitative human genome-wide map of DNA lesions induced by ultraviolet (UV) radiation, the ubiquitous carcinogen in sunlight that causes skin cancer. Remarkably, the pattern of carcinogen susceptibility across the genome of primary cells significantly reflects mutation frequency in malignant melanoma. Surprisingly, DNase-accessible euchromatin is protected from UV, while lamina-associated heterochromatin at the nuclear periphery is vulnerable. Many cancer driver genes have an intrinsic increase in carcinogen susceptibility, including the BRAF oncogene that has the highest mutation frequency in melanoma. These findings provide a genome-wide snapshot of DNA injuries at the earliest stage of carcinogenesis. Furthermore, they identify carcinogen susceptibility as an origin of genome instability that is regulated by nuclear architecture and mirrors mutagenesis in cancer.

    View details for DOI 10.15252/embj.201796717

    View details for PubMedID 28814448

    View details for PubMedCentralID PMC5623849

  • The INO80 Complex Requires the Arp5-Ies6 Subcomplex for Chromatin Remodeling and Metabolic Regulation MOLECULAR AND CELLULAR BIOLOGY Yao, W., King, D. A., Beckwith, S. L., Gowans, G. J., Yen, K., Zhou, C., Morrison, A. J. 2016; 36 (6): 979-991

    Abstract

    ATP-dependent chromatin remodeling complexes are essential for transcription regulation, and yet it is unclear how these multisubunit complexes coordinate their activities to facilitate diverse transcriptional responses. In this study, we found that the conserved Arp5 and Ies6 subunits of the Saccharomyces cerevisiae INO80 chromatin-remodeler form an abundant and distinct subcomplex in vivo and stimulate INO80-mediated activity in vitro. Moreover, our genomic studies reveal that the relative occupancy of Arp5-Ies6 correlates with nucleosome positioning at transcriptional start sites and expression levels of >1,000 INO80-regulated genes. Notably, these genes are significantly enriched in energy metabolism pathways. Specifically, arp5Δ, ies6Δ, and ino80Δ mutants demonstrate decreased expression of genes involved in glycolysis and increased expression of genes in the oxidative phosphorylation pathway. Deregulation of these metabolic pathways results in constitutively elevated mitochondrial potential and oxygen consumption. Our results illustrate the dynamic nature of the INO80 complex assembly and demonstrate for the first time that a chromatin remodeler regulates glycolytic and respiratory capacity, thereby maintaining metabolic stability.

    View details for DOI 10.1128/MCB.00801-15

    View details for Web of Science ID 000372330700011

    View details for PubMedCentralID PMC4810468

  • The INO80 Complex Requires the Arp5-Ies6 Subcomplex for Chromatin Remodeling and Metabolic Regulation. Molecular and cellular biology Yao, W., King, D. A., Beckwith, S. L., Gowans, G. J., Yen, K., Zhou, C., Morrison, A. J. 2016; 36 (6): 979-91

    Abstract

    ATP-dependent chromatin remodeling complexes are essential for transcription regulation, and yet it is unclear how these multisubunit complexes coordinate their activities to facilitate diverse transcriptional responses. In this study, we found that the conserved Arp5 and Ies6 subunits of the Saccharomyces cerevisiae INO80 chromatin-remodeler form an abundant and distinct subcomplex in vivo and stimulate INO80-mediated activity in vitro. Moreover, our genomic studies reveal that the relative occupancy of Arp5-Ies6 correlates with nucleosome positioning at transcriptional start sites and expression levels of >1,000 INO80-regulated genes. Notably, these genes are significantly enriched in energy metabolism pathways. Specifically, arp5Δ, ies6Δ, and ino80Δ mutants demonstrate decreased expression of genes involved in glycolysis and increased expression of genes in the oxidative phosphorylation pathway. Deregulation of these metabolic pathways results in constitutively elevated mitochondrial potential and oxygen consumption. Our results illustrate the dynamic nature of the INO80 complex assembly and demonstrate for the first time that a chromatin remodeler regulates glycolytic and respiratory capacity, thereby maintaining metabolic stability.

    View details for DOI 10.1128/MCB.00801-15

    View details for PubMedID 26755556

    View details for PubMedCentralID PMC4810468

  • Assembly of the Arp5 (Actin-related Protein) Subunit Involved in Distinct INO80 Chromatin Remodeling Activities JOURNAL OF BIOLOGICAL CHEMISTRY Yao, W., Beckwith, S. L., Zheng, T., Young, T., Dinh, V. T., Ranjan, A., Morrison, A. J. 2015; 290 (42): 25700-25709

    View details for DOI 10.1074/jbc.M115.674887

    View details for PubMedID 26306040

  • Association of Taf14 with acetylated histone H3 directs gene transcription and the DNA damage response. Genes & development Shanle, E. K., Andrews, F. H., Meriesh, H., McDaniel, S. L., Dronamraju, R., DiFiore, J. V., Jha, D., Wozniak, G. G., Bridgers, J. B., Kerschner, J. L., Krajewski, K., Martín, G. M., Morrison, A. J., Kutateladze, T. G., Strahl, B. D. 2015; 29 (17): 1795-1800

    Abstract

    The YEATS domain, found in a number of chromatin-associated proteins, has recently been shown to have the capacity to bind histone lysine acetylation. Here, we show that the YEATS domain of Taf14, a member of key transcriptional and chromatin-modifying complexes in yeast, is a selective reader of histone H3 Lys9 acetylation (H3K9ac). Structural analysis reveals that acetylated Lys9 is sandwiched in an aromatic cage formed by F62 and W81. Disruption of this binding in cells impairs gene transcription and the DNA damage response. Our findings establish a highly conserved acetyllysine reader function for the YEATS domain protein family and highlight the significance of this interaction for Taf14.

    View details for DOI 10.1101/gad.269977.115

    View details for PubMedID 26341557

    View details for PubMedCentralID PMC4573853

  • Transcriptome profiling of Set5 and Set1 methyltransferases: Tools for visualization of gene expression. Genomics data Martín, G. M., King, D. A., Garcia-Nieto, P. E., Morrison, A. J. 2014; 2: 216-218

    Abstract

    Cells regulate transcription by coordinating the activities of multiple histone modifying complexes. We recently identified the yeast histone H4 methyltransferase Set5 and discovered functional overlap with the histone H3 methyltransferase Set1 in gene expression. Specifically, using next-generation RNA sequencing (RNA-Seq), we found that Set5 and Set1 function synergistically to regulate specific transcriptional programs at subtelomeres and transposable elements [1]. Here we provide a comprehensive description of the methodology and analysis tools corresponding to the data deposited in NCBI's Gene Expression Omnibus (GEO) under the accession number GSE52086. This data complements the experimental methods described in Mas Martín G et al., 2014, and provides the means to explore the cooperative functions of histone H3 and H4 methyltransferases in the regulation of transcription. Furthermore, a fully annotated R code is included to enable researchers to use the following computational tools: comparison of significant differential expression (SDE) profiles; gene ontology enrichment of SDE; and enrichment of SDE relative to chromosomal features, such as centromeres, telomeres, and transposable elements. Overall, we present a bioinformatics platform that can be generally implemented for similar analyses with different datasets and in different organisms.

    View details for PubMedID 25152866

  • Set5 and Set1 cooperate to repress gene expression at telomeres and retrotransposons. Epigenetics Martín, G. M., King, D. A., Green, E. M., Garcia-Nieto, P. E., Alexander, R., Collins, S. R., Krogan, N. J., Gozani, O. P., Morrison, A. J. 2014; 9 (4): 513-522

    Abstract

    A complex interplay between multiple chromatin modifiers is critical for cells to regulate chromatin structure and accessibility during essential DNA-templated processes such as transcription. However, the coordinated activities of these chromatin modifiers in the regulation of gene expression are not fully understood. We previously determined that the budding yeast histone H4 methyltransferase Set5 functions together with Set1, the H3K4 methyltransferase, in specific cellular contexts. Here, we sought to understand the relationship between these evolutionarily conserved enzymes in the regulation of gene expression. We generated a comprehensive genetic interaction map of the functionally uncharacterized Set5 methyltransferase and expanded the existing genetic interactome of the global chromatin modifier Set1, revealing functional overlap of the two enzymes in chromatin-related networks, such as transcription. Furthermore, gene expression profiling via RNA-Seq revealed an unexpected synergistic role of Set1 and Set5 in repressing transcription of Ty transposable elements and genes located in subtelomeric regions. This study uncovers novel pathways in which the methyltransferase Set5 participates and, more importantly, reveals a partnership between Set1 and Set5 in transcriptional repression near repetitive DNA elements in budding yeast. Together, our results define a new functional relationship between histone H3 and H4 methyltransferases, whose combined activity may be implicated in preserving genomic integrity.

    View details for DOI 10.4161/epi.27645

    View details for PubMedID 24442241

    View details for PubMedCentralID PMC4121362

  • New marks on the block Set5 methylates H4 lysines 5, 8 and 12 NUCLEUS-AUSTIN Green, E. M., Morrison, A. J., Gozani, O. 2012; 3 (4): 335-339

    Abstract

    The methylation of lysine residues in the N-terminal tails of histones is a highly conserved mechanism that regulates critical functions of chromatin, such as the control of gene expression. Using a biochemical approach, we recently identified new methylation marks on the histone H4 tail in budding yeast at lysines 5, 8 and 12, catalyzed by the previously-uncharacterized enzyme Set5. Genetic studies revealed that Set5 functions in cellular processes that also rely on the global chromatin modifying complexes COMPASS and NuA4, which methylate H3 lysine 4 and acetylate H4 lysines 5, 8 and 12, respectively. The identification of new methylation events on the H4 tail raises many intriguing questions regarding their function and their interaction with known histone modifications. Here, we analyze the insights gained about the new enzyme Set5 and the implications for new functionality added to the H4 tail.

    View details for DOI 10.4161/nucl.20695

    View details for Web of Science ID 000315929000009

    View details for PubMedID 22688645

  • Chromatin remodelling beyond transcription: the INO80 and SWR1 complexes NATURE REVIEWS MOLECULAR CELL BIOLOGY Morrison, A. J., Shen, X. 2009; 10 (6): 373-384

    Abstract

    Chromatin-modifying factors have essential roles in DNA processing pathways that dictate cellular functions. The ability of chromatin modifiers, including the INO80 and SWR1 chromatin-remodelling complexes, to regulate transcriptional processes is well established. However, recent studies reveal that the INO80 and SWR1 complexes have crucial functions in many other essential processes, including DNA repair, checkpoint regulation, DNA replication, telomere maintenance and chromosome segregation. During these diverse nuclear processes, the INO80 and SWR1 complexes function cooperatively with their histone substrates, gamma-H2AX and H2AZ. This research reveals that INO80 and SWR1 ATP-dependent chromatin remodelling is an integral component of pathways that maintain genomic integrity.

    View details for DOI 10.1038/nrm2693

    View details for Web of Science ID 000266270900012

    View details for PubMedID 19424290

  • Mec1/Tel1 phosphorylation of the INO80 Chromatin Remodeling Complex Influences DNA damage checkpoint responses CELL Morrison, A. J., Kim, J., Person, M. D., Highland, J., Xiao, J., Wehr, T. S., Hensley, S., Bao, Y., Shen, J., Collins, S. R., Weissman, J. S., Delrow, J., Krogan, N. J., Haber, J. E., Shen, X. 2007; 130 (3): 499-511

    Abstract

    The yeast Mec1/Tel1 kinases, ATM/ATR in mammals, coordinate the DNA damage response by phosphorylating proteins involved in DNA repair and checkpoint pathways. Recently, ATP-dependent chromatin remodeling complexes, such as the INO80 complex, have also been implicated in DNA damage responses, although regulatory mechanisms that direct their function remain unknown. Here, we show that the Ies4 subunit of the INO80 complex is phosphorylated by the Mec1/Tel1 kinases during exposure to DNA-damaging agents. Mutation of Ies4's phosphorylation sites does not significantly affect DNA repair processes, but does influence DNA damage checkpoint responses. Additionally, ies4 phosphorylation mutants are linked to the function of checkpoint regulators, such as the replication checkpoint factors Tof1 and Rad53. These findings establish a chromatin remodeling complex as a functional component in the Mec1/Tel1 DNA damage signaling pathway that modulates checkpoint responses and suggest that posttranslational modification of chromatin remodeling complexes regulates their involvement in distinct processes.

    View details for DOI 10.1016/j.cell.2007.06.010

    View details for Web of Science ID 000249038100017

    View details for PubMedID 17693258

  • INO80 and gamma-H2AX interaction links ATP-dependent chromatin remodeling to DNA damage repair CELL Morrison, A. J., Highland, J., Krogan, N. J., Arbel-Eden, A., Greenblatt, J. F., Haber, J. E., Shen, X. T. 2004; 119 (6): 767-775

    Abstract

    While the role of ATP-dependent chromatin remodeling in transcription is well established, a link between chromatin remodeling and DNA repair has remained elusive. We have found that the evolutionarily conserved INO80 chromatin remodeling complex directly participates in the repair of a double-strand break (DSB) in yeast. The INO80 complex is recruited to a HO endonuclease-induced DSB through a specific interaction with the DNA damage-induced phosphorylated histone H2A (gamma-H2AX). This interaction requires Nhp10, an HMG-like subunit of the INO80 complex. The loss of Nhp10 or gamma-H2AX results in reduced INO80 recruitment to the DSB. Finally, components of the INO80 complex show synthetic genetic interactions with the RAD52 DNA repair pathway, the main pathway for DSB repair in yeast. Our findings reveal a new role of ATP-dependent chromatin remodeling in nuclear processes and suggest that an ATP-dependent chromatin remodeling complex can read a DNA repair histone code.

    View details for Web of Science ID 000225907200008

    View details for PubMedID 15607974

  • Rb targets histone H3 methylation and HP1 to promoters NATURE Nielsen, S. J., Schneider, R., Bauer, U. M., Bannister, A. J., Morrison, A., O'Carroll, D., Firestein, R., Cleary, M., Jenuwein, T., Herrera, R. E., Kouzarides, T. 2001; 412 (6846): 561-565

    Abstract

    In eukaryotic cells the histone methylase SUV39H1 and the methyl-lysine binding protein HP1 functionally interact to repress transcription at heterochromatic sites. Lysine 9 of histone H3 is methylated by SUV39H1 (ref. 2), creating a binding site for the chromo domain of HP1 (refs 3, 4). Here we show that SUV39H1 and HP1 are both involved in the repressive functions of the retinoblastoma (Rb) protein. Rb associates with SUV39H1 and HP1 in vivo by means of its pocket domain. SUV39H1 cooperates with Rb to repress the cyclin E promoter, and in fibroblasts that are disrupted for SUV39, the activity of the cyclin E and cyclin A2 genes are specifically elevated. Chromatin immunoprecipitations show that Rb is necessary to direct methylation of histone H3, and is necessary for binding of HP1 to the cyclin E promoter. These results indicate that the SUV39H1-HP1 complex is not only involved in heterochromatic silencing but also has a role in repression of euchromatic genes by Rb and perhaps other co-repressor proteins.

    View details for Web of Science ID 000170202900051

    View details for PubMedID 11484059