About

Professor Brian D. Strahl leads the Strahl lab at the University of North Carolina at Chapel Hill, within the School of Medicine. His research focuses on unraveling the fundamental mechanisms that drive chromatin biology, with a particular emphasis on understanding how histones, histone modifications, histone chaperones, and chromatin-remodeling enzymes precisely organize and control the genome. This regulation is essential for proper gene expression, cell growth and differentiation, development, and the ability to respond to environmental changes. The lab aims to define the mechanisms by which histones, their post-translational modifications (PTMs), and other chromatin-associated complexes contribute to human biology and disease. Histone modifications, whether acting alone or in combination, play crucial roles in gene transcription and heterochromatin formation, yet their exact contributions and how they contribute to human disease remain poorly understood. To address these unresolved questions, the Strahl lab employs Saccharomyces cerevisiae (yeast) and mammalian cell models, integrating genetic, biochemical, proteomic, and genomic methodologies. The research areas include defining how histone modifying enzymes and chaperones contribute to chromatin organization and gene transcription, uncovering the role of histone modifications and readers in metabolic gene transcription, and defining the rules by which chromatin regulators engage nucleosomes to regulate chromatin biology. The lab is committed to fostering a safe, inclusive, and supportive environment for all individuals, welcoming people from all groups and backgrounds, and affirming that a respectful and accommodating environment promotes the highest quality science and training for success.

Research topics

• Genetics
• Biology
• Cell biology
• Computational biology
• Botany
• Nanotechnology
• Chemistry
• Physics
• Evolutionary biology
• Optics

Selected publications

• Casein Kinase II Phosphorylation of Spt6 Enforces Transcriptional Fidelity by Maintaining Spn1-Spt6 Interaction

  UNC Libraries · 2026-04-14

  articleOpen access1st authorCorresponding
  PublisherDOI

• Rapid CRISPR–Cas9 Genome Editing in S. cerevisiae

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-30 · 1 citations

  articleOpen accessSenior authorCorresponding

  This protocol enables rapid CRISPR-Cas9 genome editing in Saccharomyces cerevisiae by replacing restriction/ligation guide cloning with PCR-based protospacer installation and seamless plasmid recircularization. It describes in silico HDR donor and SgRNA design, install guide sequences into cas9 plasmid by PCR and seamless assembly, plasmid cloning and sequence verification in E. coli, and LiAc/PEG co-transformation of yeast with Cas9-sgRNA plasmid plus HDR donor. The workflow selects yeast colonies on G418 and confirms edits by PCR and sequencing.

  PublisherOA PDFDOI

• Tandem bromodomains of BRD4 cooperatively read poly-acetylated nucleosomes to enhance chromatin engagement and regulate breast cancer phenotypes

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-24

  articleOpen accessSenior authorCorresponding

  Abstract Bromodomain-containing protein 4 (BRD4) is an acetyl-lysine reader protein implicated in transcriptional control and oncogenesis, yet how its tandem bromodomains (BD1-2) contribute to nucleosomal engagement remains unresolved. Here we show that the tandem bromodomains of BRD4 cooperatively engage poly-acetylated histone H4 tails and nucleosomes in vitro and promote chromatin association in human cells. In stringent peptide pull-down and nucleosome-based biolayer interferometry assays, isolated BRD4 bromodomains bind weakly to poly-acetylated histone peptides and nucleosomes, whereas the tandem BD1-2 module binds much more robustly. These results closely mirror our observations in mammalian cells, where truncations lacking either bromodomain or pocket-disrupting mutations in either domain reduced chromatin association, with dual pocket disruption causing the strongest defect. In the BRD4 short isoform (BRD4-S), maximal chromatin association additionally required the region C-terminal to the BD2, which contains the basic residue-enriched interaction domain (BID) and extraterminal domain (ET), consistent with a multivalent chromatin engagement mechanism beyond the bromodomains alone. Functionally, dual pocket disruption attenuated BRD4-S-dependent breast cancer phenotypes, including impaired growth and reduced transwell migration. Together, these findings define how tandem bromodomains and adjacent BRD4-S regions cooperate to stabilize chromatin residence and inform therapeutic strategies aimed at more precisely disrupting BRD4 function. Graphical Abstract

  PublisherOA PDFDOI

• Spt6-Spn1 interaction is required for RNA polymerase II association and precise nucleosome positioning along transcribed genes

  Journal of Biological Chemistry · 2025-03-22 · 3 citations

  articleOpen accessSenior author

  Spt6-Spn1 is an essential histone chaperone complex that associates with RNA Polymerase II (RNAPII) and reassembles nucleosomes during gene transcription. While the interaction between Spt6 and Spn1 is important for its histone deposition and transcription functions, a precise mechanistic understanding is still limited. Here, using temperature-sensitive alleles of spt6 and spn1 that disrupt their interaction in yeast, we show that the Spt6-Spn1 association is important for its stable interaction with the elongating RNAPII complex and nucleosomes. Using micrococcal nuclease (MNase)-based chromatin occupancy profiling, we further find that Spt6-Spn1 interaction is required to maintain a preferred nucleosome positioning at actively transcribed genes; in the absence of Spt6-Spn1 interaction, we observe a return to replication-dependent phasing. In addition to positioning defects, Spt6-Spn1 disrupting mutants also resulted in an overall shift of nucleosomes toward the 5' end of genes that were correlated with decreased RNAPII levels. As loss of Spt6-Spn1 association results in cryptic transcription at a subset of genes, we examined these genes for their nucleosome profiles. These findings revealed that the chromatin organization at these loci is similar to other active genes, thus underscoring the critical role of DNA sequence in mediating cryptic transcription when nucleosome positioning is altered. Taken together, these findings reveal that Spt6-Spn1 interaction is key to its association with elongating RNAPII and to its ability to precisely organize nucleosomes across transcription units.

  PublisherOA PDFDOI

• Written in chromatin: The enduring legacy of C. David Allis

  Journal of Biological Chemistry · 2025-07-01 · 1 citations

  editorialOpen access1st authorCorresponding
  PublisherDOI

• Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation

  Nature Communications · 2025-03-06 · 3 citations

  articleOpen access

  Abstract The histone H3K36-specific methyltransferase ASH1L plays a critical role in development and is frequently dysregulated in human diseases, particularly cancer. Here, we report on the biological functions of the C-terminal region of ASH1L encompassing a bromodomain (ASH1L BD ), a plant homeodomain (ASH1L PHD ) finger, and a bromo-adjacent homology (ASH1L BAH ) domain, structurally characterize these domains, describe their mechanisms of action, and explore functional crosstalk between them. We find that ASH1L PHD recognizes H3K4me2/3, whereas the neighboring ASH1L BD and ASH1L BAH have DNA binding activities. The DNA binding function of ASH1L BAH is a driving force for the association of ASH1L with the linker DNA in the nucleosome, and the large interface with ASH1L PHD stabilizes the ASH1L BAH fold, merging two domains into a single module. We show that ASH1L is involved in embryonic stem cell differentiation and co-localizes with H3K4me3 but not with H3K36me2 at transcription start sites of target genes and genome wide, and that the interaction of ASH1L PHD with H3K4me3 is inhibitory to the H3K36me2-specific catalytic activity of ASH1L. Our findings shed light on the mechanistic details by which the C-terminal domains of ASH1L associate with chromatin and regulate the enzymatic function of ASH1L.

  PublisherOA PDFDOI

• SETD2 suppresses tumorigenesis in a KRASG12C-driven lung cancer model and its catalytic activity is regulated by histone acetylation

  eLife · 2025-07-09

  preprintOpen access

  Abstract Histone H3 trimethylation at lysine 36 (H3K36me3) is a key chromatin modification that regulates fundamental physiologic and pathologic processes. In humans, SETD2 is the only known enzyme that catalyzes H3K36me3 in somatic cells and is implicated in tumor suppression across multiple cancer types. While there is considerable crosstalk between the SETD2-H3K36me3 axis and other epigenetic modifications, much remains to be understood. Here, we show that SETD2 functions as a potent tumor suppressor in a KRASG12C-driven lung adenocarcinoma (LUAD) mouse model, and that acetylation at H3K27 (H3K27ac) enhances SETD2 in vitro methylation of H3K36 on nucleosome substrates. In vivo, SETD2 ablation accelerates lethality in an autochthonous KRASG12C-driven LUAD mouse tumor model. Biochemical analyses reveal that polyacetylation of histone tails in a nucleosome context promote H3K36 methylation by SETD2. In addition, monoacetylation exerts position-specific effects to stimulate SETD2 methylation activity. In contrast, mono-ubiquitination at various histone sites, including at H2AK119 and H2BK120, does not affect SETD2 methylation of nucleosomes. Together, these findings provide insight into how SETD2 integrates histone modification signals to regulate H3K36 methylation and highlights the potential role of SETD2-associated epigenetic crosstalk in cancer pathogenesis.

  PublisherDOI

• A needed nomenclature for nucleosomes

  Molecular Cell · 2025-10-01 · 9 citations

  reviewOpen access
  PublisherOA PDFDOI

• SETD2 suppresses tumorigenesis in a KRAS ^G12C -driven lung cancer model and its catalytic activity is regulated by histone acetylation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-18

  preprintOpen access

  ABSTRACT Histone H3 trimethylation at lysine 36 (H3K36me3) is a key chromatin modification that regulates fundamental physiologic and pathologic processes. In humans, SETD2 is the only known enzyme that catalyzes H3K36me3 in somatic cells and is implicated in tumor suppression across multiple cancer types. While there is considerable crosstalk between the SETD2-H3K36me3 axis and other epigenetic modifications, much remains to be understood. Here, we show that SETD2 functions as a potent tumor suppressor in a KRAS G12C -driven lung adenocarcinoma (LUAD) mouse model, and that acetylation enhances SETD2 in vitro methylation of H3K36 on nucleosome substrates. In vivo , SETD2 ablation accelerates lethality in an autochthonous KRAS G12C -driven LUAD mouse tumor model. Biochemical analyses reveal that polyacetylation of histone tails in a nucleosome context promote H3K36 methylation by SETD2. In addition, monoacetylation exerts position-specific effects to stimulate SETD2 methylation activity. In contrast, mono-ubiquitination at various histone sites, including at H2AK119 and H2BK120, does not affect SETD2 methylation of nucleosomes. Together, these findings provide insight into how SETD2 integrates histone modification signals to regulate H3K36 methylation and highlights the potential role of SETD2-associated epigenetic crosstalk in cancer pathogenesis.

  PublisherOA PDFDOI

• Abstract 1798 Histone H3 N-terminal recognition by the PHD finger of PHRF1 is required for proper DNA damage response

  Journal of Biological Chemistry · 2025-05-01

  articleOpen accessSenior author

  Plant homeodomain (PHD) fingers are critical effectors of histone post-translational modifications (PTMs), acting as regulators of gene expression and genome integrity, and frequently presenting in human disease. While most PHD fingers recognize unmodified and methylated states of histone H3 lysine 4 (H3K4), the specific functions of many of the over 100 PHD finger-containing proteins in humans remain poorly understood, despite their significant implications in disease processes. In this study, we undertook a comprehensive analysis of one such poorly characterized PHD finger-containing protein, PHRF1.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01GM085394

  NIH · $1.2M · 2012

• Role of Dot1 and H3K79 methylation in gene regulation

  NSF · $750k · 2013–2016

• Chromatin maintenance in cancer progression

  NIH · $2.3M · 2015–2022

• NIH Grant R01GM068088

  NIH · $3.4M · 2018

• Mechanisms of chromatin and transcriptional regulation

  NIH · $5.5M · 2018–2028

Frequent coauthors

• Scott B. Rothbart

  Van Andel Institute

  89 shared

• Krzysztof Krajewski

  69 shared

• Ian J. Davis

  University of North Carolina at Chapel Hill

  62 shared

• Tatiana G. Kutateladze

  University of Colorado Denver

  50 shared

• Raghuvar Dronamraju

  University of North Carolina at Chapel Hill

  42 shared

• Robert J. Duronio

  40 shared

• A. Gregory Matera

  University of North Carolina at Chapel Hill

  37 shared

• Stephen M. Fuchs

  Boston Children's Hospital

  31 shared

Education

• Ph.D., Molecular and Cell Biology

  University of California, San Francisco

  2004

• B.S., Molecular and Cell Biology

  University of California, Berkeley

  1999

Awards & honors

• UNC Excellence in Basic Science Mentoring Award (2019)
• UNC Oliver Smithies Investigator (2018)
• NIH Maximizing Investigators' Research Award (MIRA) (2018)
• Philip & Ruth Hettleman Prize (2009)
• NIH Exceptional, Unconventional Research Enabling Knowledge…