Jeremy Tzu-Huai Chang, MD, PhD

All Publications

• Molecular determinants of Smc5/6 association with DNA junctions. Nature communications Chang, J. T., Miller-Browne, V., Chua, G. N., Zheng, J., Beckwitt, E. C., Li, S., Katch, B. J., O'Donnell, M. E., Liu, S., Zhao, X. 2026; 17 (1): 1239

  Abstract

  Smc5/6 is an essential genome maintenance complex that interacts with double-stranded (ds) DNA, single-stranded (ss) DNA, and ss-dsDNA junctions. DNA association underlies Smc5/6's functions in managing intermediates generated during genome replication and repair. However, the mechanisms of this activity are not fully understood. Here, we report a single-molecule study examining Smc5/6 association with a dsDNA substrate containing a ssDNA gap with defined 3' and 5' junctions. We found that Smc5/6 associates with both 3' and 5' junctions but prefers the 3' junction in the presence of the ssDNA-binding complex RPA. Further, Smc5/6's junction association frequency and dwell time are regulated by two non-SMC subcomplexes and DNA binding residues of Smc6. Moreover, Smc5/6 prefers binding to junction sites free of the sliding clamp PCNA over those occupied with it. These results suggest that Smc5/6 utilizes its multiple structural modules to associate with junction sites in coordination with other genome maintenance factors.

  View details for DOI 10.1038/s41467-025-67999-5

  View details for PubMedID 41547900

  View details for PubMedCentralID PMC12864806

• Signaling induced biophysical disruption of repressed chromatin domains drives immune cell fate. bioRxiv : the preprint server for biology de Paz, A. M., Chin, C. R., Ketavarapu, M., Sun, Y., Marunde, M. R., Chang, J. T., Khan, L., Cohen, J., Yang, R., Bale, M. J., Daman, A. W., Kumar, V. E., Jiang, C., Ahimovic, D. J., Owyong, M., Ravishankar, A., Wong, W., Shih, R., Graham, B., Smith, C. E., Karagianidis, I., Cerchietti, L., Flowers, C. R., Green, M. R., Mason, C. E., Sun, J. C., Martin-Trujillo, A., Niec, R. E., Long, Y., Keogh, M. C., Liu, S., Béguelin, W., Leslie, C. S., Melnick, A. M., Josefowicz, S. Z. 2025

  Abstract

  Cell fate transitions require signal-induced chromatin derepression, yet mechanisms governing transitions from repressed to active chromatin states are poorly understood. We discover, at fate-defining genes across immune cell types, a signal-induced histone code, and describe domains of H3 serine 28 phosphorylation (H3S28ph) spanning architectural features, often coincident with repressive H3 lysine 27 trimethylation (H3K27me3). Employing biophysical, single cell, and functional approaches to study signal-induced cell differentiation in the immune system, we uncover epigenomic transitions and cell fate choices precipitated by histone phosphorylation (H3ph). Mechanistically, H3ph overrides Polycomb Repressive Complex 2 (PRC2) chromatin repression, biophysically disrupts polynucleosome compaction, and promotes loss of H3K27me3, while increasing activating H3K27 acetylation and H3K36 dimethylation to drive domain interactivity and stabilize transcription. We demonstrate the activity of H3ph in several cell fate transitions and illuminate biophysical mechanisms enabling rapid signal-activated chromatin derepression, processes with general relevance for cellular differentiation and activation.

  View details for DOI 10.64898/2025.12.08.692984

  View details for PubMedID 41427328

  View details for PubMedCentralID PMC12713132

• Smc5/6's multifaceted DNA binding capacities stabilize branched DNA structures. Nature communications Chang, J. T., Li, S., Beckwitt, E. C., Than, T., Haluska, C., Chandanani, J., O'Donnell, M. E., Zhao, X., Liu, S. 2022; 13 (1): 7179

  Abstract

  Smc5/6 is an evolutionarily conserved SMC complex with roles in DNA replication and repair, as well as in viral DNA restriction. Understanding its multiple functions has been hampered by a lack of mechanistic studies on how the Smc5/6 complex associates with different types of DNA. Here we address this question by simultaneously visualizing the behavior of Smc5/6 on three types of DNA, namely double-stranded (ds) DNA, single-stranded (ss) DNA, and junction DNA formed by juxtaposed ss- and dsDNA, using correlative single-molecule fluorescence and force microscopy. We find that Smc5/6 displays distinct behaviors toward different types of DNA, dynamically associating with dsDNA while stably binding to junction DNA. Mechanistically, both the Nse1-3-4 subcomplex and ATP binding enhance the complex's dsDNA association. In contrast, Smc5/6's assembly onto ssDNA emanating from junction DNA, which occurs even in the presence high-affinity ssDNA binders, is aided by Nse1-3-4, but not by ATP. Moreover, we show that Smc5/6 protects junction DNA stability by preventing ssDNA annealing. The multifaceted DNA association behaviors of Smc5/6 provide a framework for understanding its diverse functions in genome maintenance and viral DNA restriction.

  View details for DOI 10.1038/s41467-022-34928-9

  View details for PubMedID 36418314

  View details for PubMedCentralID PMC9684126

• Chromatin sequesters pioneer transcription factor Sox2 from exerting force on DNA. Nature communications Nguyen, T., Li, S., Chang, J. T., Watters, J. W., Ng, H., Osunsade, A., David, Y., Liu, S. 2022; 13 (1): 3988

  Abstract

  Biomolecular condensation constitutes an emerging mechanism for transcriptional regulation. Recent studies suggest that the co-condensation between transcription factors (TFs) and DNA can generate mechanical forces driving genome rearrangements. However, the reported forces generated by protein-DNA co-condensation are typically below one piconewton (pN), questioning its physiological significance. Moreover, the force-generating capacity of these condensates in the chromatin context remains unknown. Here, we show that Sox2, a nucleosome-binding pioneer TF, forms co-condensates with DNA and generates forces up to 7 pN, exerting considerable mechanical tension on DNA strands. We find that the disordered domains of Sox2 are required for maximum force generation but not for condensate formation. Furthermore, we show that nucleosomes dramatically attenuate the mechanical stress exerted by Sox2 by sequestering it from coalescing on bare DNA. Our findings reveal that TF-mediated DNA condensation can exert significant mechanical stress on the genome which can nonetheless be attenuated by the chromatin architecture.

  View details for DOI 10.1038/s41467-022-31738-x

  View details for PubMedID 35810158

  View details for PubMedCentralID PMC9271091

• iMIRAGE: an R package to impute microRNA expression using protein-coding genes. Bioinformatics (Oxford, England) Nath, A., Chang, J., Huang, R. S. 2020; 36 (8): 2608-2610

  Abstract

  MicroRNAs (miRNAs) are critical post-transcriptional regulators of gene expression. Due to challenges in accurate profiling of small RNAs, a vast majority of public transcriptome datasets lack reliable miRNA profiles. However, the biological consequence of miRNA activity in the form of altered protein-coding gene (PCG) expression can be captured using machine-learning algorithms. Here, we present iMIRAGE (imputed miRNA activity from gene expression), a convenient tool to predict miRNA expression using PCG expression of the test datasets. The iMIRAGE package provides an integrated workflow for normalization and transformation of miRNA and PCG expression data, along with the option to utilize predicted miRNA targets to impute miRNA activity from independent test PCG datasets.The iMIRAGE package for R, along with package documentation and vignette, is available at https://aritronath.github.io/iMIRAGE/index.html.Supplementary data are available at Bioinformatics online.

  View details for DOI 10.1093/bioinformatics/btz939

  View details for PubMedID 31860075

  View details for PubMedCentralID PMC7828470

• Low Referral Rate for Genetic Testing in Racially and Ethnically Diverse Patients Despite Universal Colorectal Cancer Screening. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Muller, C., Lee, S. M., Barge, W., Siddique, S. M., Berera, S., Wideroff, G., Tondon, R., Chang, J., Peterson, M., Stoll, J., Katona, B. W., Sussman, D. A., Melson, J., Kupfer, S. S. 2018; 16 (12): 1911-1918.e2

  Abstract

  Guidelines recommend that all colorectal tumors be assessed for mismatch repair deficiency, which could increase identification of patients with Lynch syndrome. This is of particular importance for minority populations, in whom hereditary syndromes are under diagnosed. We compared rates and outcomes of testing all tumor samples (universal testing) collected from a racially and ethnically diverse population for features of Lynch syndrome.We performed a retrospective analysis of colorectal tumors tested from 2012 through 2016 at 4 academic centers. Tumor samples were collected from 767 patients with colorectal cancer (52% non-Hispanic white [NHW], 26% African American, and 17% Hispanic patients). We assessed rates of tumor testing, recommendations for genetic evaluation, rates of attending a genetic evaluation, and performance of germline testing overall and by race/ethnicity. We performed univariate and multivariate regression analyses.Overall, 92% of colorectal tumors were analyzed for mismatch repair deficiency without significant differences among races/ethnicities. However, minority patients were significantly less likely to be referred for genetic evaluation (21.2% for NHW patients vs 16.9% for African American patients and 10.9% for Hispanic patients; P = .02). Rates of genetic testing were also lower among minority patients (10.7% for NHW patients vs 6.0% for AA patients and 3.1% for Hispanic patients; P < .01). On multivariate analysis, African American race, older age, and medical center were independently associated with lack of referral for genetic evaluation and genetic testing.In a retrospective analysis, we found that despite similar rates of colorectal tumor analysis, minority patients are less likely to be recommended for genetic evaluation or to undergo germline testing for Lynch syndrome. Improvements in institutional practices in follow up after tumor testing could reduce barriers to diagnosis of Lynch diagnosis in minorities.

  View details for DOI 10.1016/j.cgh.2018.08.038

  View details for PubMedID 30130624

  View details for PubMedCentralID PMC6866232

• Discovering drugs to overcome chemoresistance in ovarian cancers based on the cancer genome atlas tumor transcriptome profile. Oncotarget Wang, F., Chang, J. T., Zhang, Z., Morrison, G., Nath, A., Bhutra, S., Huang, R. S. 2017; 8 (70): 115102-115113

  Abstract

  Ovarian cancer accounts for the highest mortality among gynecologic cancers, mainly due to intrinsic or acquired chemoresistance. While mechanistic-based methods have been used to identify compounds that can overcome chemoresistance, an effective comprehensive drug screening has yet to be developed. We applied a transcriptome based drug sensitivity prediction method, to the Cancer Genome Atlas (TCGA) ovarian cancer dataset to impute patient tumor response to over 100 different drugs. By stratifying patients based on their predicted response to standard of care (SOC) chemotherapy, we identified drugs that are likely more sensitive in SOC resistant ovarian tumors. Five drugs (ABT-888, BIBW2992, gefitinib, AZD6244 and lenalidomide) exhibit higher efficacy in SOC resistant ovarian tumors when multi-platform of transcriptome profiling methods were employed. Additional in vitro and clinical sample validations were carried out and verified the effectiveness of these agents. Our candidate drugs hold great potential to improve clinical outcome of chemoresistant ovarian cancer.

  View details for DOI 10.18632/oncotarget.22870

  View details for PubMedID 29383145

  View details for PubMedCentralID PMC5777757

• Identification of MicroRNAs as Breast Cancer Prognosis Markers through the Cancer Genome Atlas. PloS one Chang, J. T., Wang, F., Chapin, W., Huang, R. S. 2016; 11 (12): e0168284

  Abstract

  Breast cancer is the second-most common cancer and second-leading cause of cancer mortality in American women. The dysregulation of microRNAs (miRNAs) plays a key role in almost all cancers, including breast cancer. We comprehensively analyzed miRNA expression, global gene expression, and patient survival from the Cancer Genomes Atlas (TCGA) to identify clinically relevant miRNAs and their potential gene targets in breast tumors. In our analysis, we found that increased expression of 12 mature miRNAs-hsa-miR-320a, hsa-miR-361-5p, hsa-miR-103a-3p, hsa-miR-21-5p, hsa-miR-374b-5p, hsa-miR-140-3p, hsa-miR-25-3p, hsa-miR-651-5p, hsa-miR-200c-3p, hsa-miR-30a-5p, hsa-miR-30c-5p, and hsa-let-7i-5p -each predicted improved breast cancer survival. Of the 12 miRNAs, miR-320a, miR-361-5p, miR-21-5p, miR-103a-3p were selected for further analysis. By correlating global gene expression with miRNA expression and then employing miRNA target prediction analysis, we suggest that the four miRNAs may exert protective phenotypes by targeting breast oncogenes that contribute to patient survival. We propose that miR-320a targets the survival-associated genes RAD51, RRP1B, and TDG; miR-361-5p targets ARCN1; and miR-21-5p targets MSH2, RMND5A, STAG2, and UBE2D3. The results of our stringent bioinformatics approach for identifying clinically relevant miRNAs and their targets indicate that miR-320a, miR-361-5p, and miR-21-5p may contribute to breast cancer survival.

  View details for DOI 10.1371/journal.pone.0168284

  View details for PubMedID 27959953

  View details for PubMedCentralID PMC5154569

• High Expression of miR-532-5p, a Tumor Suppressor, Leads to Better Prognosis in Ovarian Cancer Both In Vivo and In Vitro. Molecular cancer therapeutics Wang, F., Chang, J. T., Kao, C. J., Huang, R. S. 2016; 15 (5): 1123-31

  Abstract

  Ovarian cancer is the leading cause of death for gynecologic cancers, ranking fifth overall for cancer-related death among women. The identification of biomarkers and the elucidation of molecular mechanisms for improving treatment options have received extensive efforts in ovarian cancer research. miRNAs have high potential to act as both ovarian cancer biomarkers and as critical regulators of ovarian tumor behavior. We comprehensively analyzed global mRNA, miRNA expression, and survival data for ovarian cancer from The Cancer Genome Atlas (TCGA) to pinpoint miRNAs that play critical roles in ovarian cancer survival through their effect on mRNA expression. We performed miRNA overexpression and gene knockdown experiments to confirm mechanisms predicted in our bioinformatics approach. We established that overexpression of miR-532-5p in OVCAR-3 cells resulted in a significant decrease in cell viability over a 96-hour time period. In the TCGA ovarian cancer dataset, we found 67 genes whose expression levels were negatively correlated with miR-532-5p expression and correlated with patient survival, such as WNT9A, CSNK2A2, CHD4, and SH3PXD2A The potential miR-532-5p-regulated gene targets were found to be enriched in the Wnt pathway. Overexpression of miR-532-5p through miRNA mimic caused downregulation of CSNK2A2, CHD4, and SH3PXD2A in the OVCAR-3 cell line. We have discovered and validated the tumor-suppressing capabilities of miR-532-5p both in vivo through TCGA analysis and in vitro through ovarian cancer cell lines. Our work highlights the potential clinical importance of miR-532-5p expression in ovarian cancer patients. Mol Cancer Ther; 15(5); 1123-31. ©2016 AACR.

  View details for DOI 10.1158/1535-7163.MCT-15-0943

  View details for PubMedID 26873729

  View details for PubMedCentralID PMC4873383

• The impact of the Cancer Genome Atlas on lung cancer. Translational research : the journal of laboratory and clinical medicine Chang, J. T., Lee, Y. M., Huang, R. S. 2015; 166 (6): 568-85

  Abstract

  The Cancer Genome Atlas (TCGA) has profiled more than 10,000 samples derived from 33 types of cancer to date, with the goal of improving our understanding of the molecular basis of cancer and advancing our ability to diagnose, treat, and prevent cancer. This review focuses on lung cancer as it is the leading cause of cancer-related mortality worldwide in both men and women. Particularly, non-small cell lung cancers (including lung adenocarcinoma and lung squamous cell carcinoma) were evaluated. Our goal was to demonstrate the impact of TCGA on lung cancer research under 4 themes: diagnostic markers, disease progression markers, novel therapeutic targets, and novel tools. Examples are given related to DNA mutation, copy number variation, messenger RNA, and microRNA expression along with methylation profiling.

  View details for DOI 10.1016/j.trsl.2015.08.001

  View details for PubMedID 26318634

  View details for PubMedCentralID PMC4656061