Honors & Awards
Pathways to Independence Award (K99/R00), NIH (2009-2012)
Kimmel Scholar Award, Sidney Kimmel Foundation for Cancer Research (2010-2012)
Terman Fellow Award, Hewlett Foundation (2010-2013)
Ph.D., Baylor College of Medicine, Biomedical Sciences (2004)
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.
- Chromatin Regulation of the Genome
BIO 110, BIO 210 (Spr)
Independent Studies (10)
- Advanced Research Laboratory in Experimental Biology
BIO 199 (Aut, Win, Spr, Sum)
- Directed Reading in Biology
BIO 198 (Aut, Win, Spr, Sum)
- Directed Reading in Cancer Biology
CBIO 299 (Aut, Win, Spr, Sum)
- Graduate Research
BIO 300 (Aut, Win, Spr, Sum)
- Graduate Research
CBIO 399 (Aut, Win, Spr, Sum)
- Out-of-Department Advanced Research Laboratory in Experimental Biology
BIO 199X (Sum)
- Out-of-Department Directed Reading
BIO 198X (Aut, Win, Spr, Sum)
- Out-of-Department Graduate Research
BIO 300X (Win, Spr, Sum)
- Teaching in Cancer Biology
CBIO 260 (Spr)
- Teaching of Biology
BIO 290 (Aut, Win, Spr)
- Advanced Research Laboratory in Experimental Biology
- Prior Year Courses
Graduate and Fellowship Programs
Biology (School of Humanities and Sciences) (Phd Program)
The INO80 Complex Requires the Arp5-Ies6 Subcomplex for Chromatin Remodeling and Metabolic Regulation
MOLECULAR AND CELLULAR BIOLOGY
2016; 36 (6): 979-991
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
- Assembly of the Arp5 (Actin-related Protein) Subunit Involved in Distinct INO80 Chromatin Remodeling Activities JOURNAL OF BIOLOGICAL CHEMISTRY 2015; 290 (42): 25700-25709
Association of Taf14 with acetylated histone H3 directs gene transcription and the DNA damage response.
Genes & development
2015; 29 (17): 1795-1800
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
Transcriptome profiling of Set5 and Set1 methyltransferases: Tools for visualization of gene expression.
2014; 2: 216-218
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 . 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
View details for PubMedCentralID PMC4140983
Set5 and Set1 cooperate to repress gene expression at telomeres and retrotransposons.
2014; 9 (4): 513-522
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
2012; 3 (4): 335-339
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
2009; 10 (6): 373-384
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
2007; 130 (3): 499-511
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
2004; 119 (6): 767-775
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
2001; 412 (6846): 561-565
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