Jacob G. Kirkland, Ph.D.

Rewriting the Rules of Gene Control in Cancer and Aging

Our DNA acts like an instruction manual, but in cancer, the body sometimes opens the wrong pages. The Kirkland Lab studies how specialized “chromatin regulator” proteins control which genes turn on or off, and how failures in this system drive diseases such as breast cancer. By developing powerful tools, we can watch these molecular switches at work in real time and uncover why some tumors resist chemotherapy. Beyond cancer, we collaborate with OMRF scientists to explore how chromatin misregulation accelerates brain inflammation and ovarian aging, revealing new ways to restore tissue health.

Our ultimate goal is personalized medicine: matching the right treatment to the right patient and discovering therapies that target the root causes of cancer and age-related disease.

Epigenome Engineering and Mechanistic Dissection of mSWI/SNF Complexes

mSWI/SNF (BAF) complexes are among the most frequently mutated chromatin regulators in cancer (~20% of tumors). Traditional in vitro assays have been limited in resolving how these complexes function on native, developmentally relevant chromatin. To overcome this, I developed the FIRE-Cas9 epigenome-engineering system, enabling locus-specific recruitment of chromatin regulators and real-time measurement of their effects on chromatin structure and gene regulation on physiologic templates (Nat Commun). Building on this, our recent work in Life Science Alliance demonstrates that distinct BAF assemblies differentially modulate polycomb-associated histone marks, with canonical BAF (cBAF) uniquely opposing polycomb repression compared to pBAF and gBAF. Together, these technologies and mechanistic insights define how specific BAF configurations control chromatin state, providing a foundation for targeting BAF dysfunction in cancer.

Assembly and Function of Distinct BAF Complexes

The mammalian SWI/SNF (BAF) family of chromatin regulators comprises three major assemblies in stem cells—canonical BAF (cBAF), polybromo-associated BAF (pBAF), and GLTSCR-associated BAF (gBAF)—each sharing core subunits but incorporating unique components that confer specialized functions. pBAF-specific subunits such as PBRM1, ARID2, BRD7, and PHF10 contain multiple chromatin- and DNA-binding domains that may guide genomic targeting. While loss of ARID2 abolishes pBAF assembly, loss of PBRM1 does not, highlighting complex structural interdependence. Because pBAF is essential for normal development and frequently mutated in cancer, elucidating its assembly and activity will clarify how combinatorial BAF architecture governs gene regulation and disease.

Chromatin Regulators and Anthracycline Response in Breast Cancer

Copy-number variation (CNV) drives many breast cancers, yet its origins remain unclear. In collaboration with Christina Curtis’s lab (Nat Med), I investigated how chromatin regulators (CRGs) influence CNV and anthracycline response. Bridging computational and experimental approaches, I performed all wet-lab studies revealing that CRGs form a breast-cancer–specific transcriptional network encompassing trithorax and polycomb members. Integrating systems biology with patient data, we found that CRGs promoting DNA accessibility—such as trithorax components—predict anthracycline sensitivity, whereas repressive CRGs correlate with resistance. Experimental validation identified KDM4B as a modulator of TOP2 chromatin access, uncovering a new mechanism of anthracycline resistance. This chromatin regulatory network provides a framework for predicting TOP2-inhibitor response and developing new therapeutic strategies.

Education
B.A. in molecular and cell biology, Univ. of California, Berkeley, 2003
Ph.D. in molecular, cell and developmental biology, Univ. of California, Santa Cruz, 2013
Postdoctoral Scholar, Stanford University, 2014-2021

Honors & Awards
University of California, Santa Cruz Graduate Trainee Award, 2008-2010
President’s Dissertation Year Fellowship, University of California, 2012-2013
American Society for Cell Biology Travel Award, 2013
Stanford University Tumor Biology Trainee Award, 2014-2016
Stephen M. Prescott Endowment Fund for the Best and Brightest, 2022

Memberships
American Association for Cancer Research
American Society of Cell Biologists
American Society for Biochemistry and Molecular Biology
Society for Advancement of Chicanos/Hispanics & Native Americans in Science

Joined OMRF scientific staff in 2021

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Recent Publications

Park J, Kirkland JG. The role of the Polybromo-associated BAF complex in development. Biochem Cell Biol, 2024 November, PMID: 39541575, PMCID: PMC11752563

Bergwell M, Park J, Kirkland JG. Differential modulation of polycomb-associated histone marks by cBAF, pBAF, and gBAF complexes. Life Sci Alliance 7, 2024 August, PMID: 39209535, PMCID: PMC11361369

Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M, O'Hara SP, LaRusso NF, Miller JD, Roos CM, Verzosa GC, LeBrasseur NK, Wren JD, Farr JN, Khosla S, Stout MB, McGowan SJ, Fuhrmann-Stroissnigg H, Gurkar AU, Zhao J, Colangelo D, Dorronsoro A, Ling YY, Barghouthy AS, Navarro DC, Sano T, Robbins PD, Niedernhofer LJ, Kirkland JL. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14:644-58, 2015 August, PMID: 25754370, PMCID: PMC4531078

Selected Publications

Seoane JA*, Kirkland JG*, Caswell-Jin JL, Crabtree GR, Curtis C. Chromatin regulators mediate anthracycline sensitivity in breast cancer. Nat Med. 2019 Nov;25(11):1721-1727. Epub 2019 Nov 7. (Co-first authors) PMID: 31700186 PMCID: PMC7220800

Braun SMG*, Kirkland JG*, Chory EJ, Husmann D, Calarco JP, Crabtree GR. Rapid and reversible epigenome editing by endogenous chromatin regulators. Nat Commun. 2017 Sep 15;8(1):560. (*Co-first authors) PMID: 28916764 PMCID: PMC5601922

Hodges C, Kirkland JG, Crabtree GR. The Many Roles of BAF (mSWI/SNF) and PBAF Complexes in Cancer. Cold Spring Harb Perspect Med. 2016 Aug 1;6(8):a026930. PMID: 27413115 PMCID: PMC4968166

Kirkland JG*, Peterson MR*, Still CD 2^nd*, Brueggeman L*, Dhillon N, Kamakaka RT. Heterochromatin formation via recruitment of DNA repair proteins. Mol Biol Cell. 2015 Apr 1;26(7):1395-410. Epub 2015 Jan 28. (Co-first authors) PMID: 25631822 PMCID: PMC4454184

Kirkland JG, Kamakaka RT. Long-range heterochromatin association is mediated by silencing and double-strand DNA break repair proteins. J Cell Biol. 2013 Jun 10;201(6):809-26. PMID: 23733345, PMCID: PMC3678155

Kirkland JG, Raab JR, Kamakaka RT. TFIIIC bound DNA elements in nuclear organization and insulation. Biochim Biophys Acta. 2013 Mar-Apr;1829(3-4):418-24. doi: 10.1016/j.bbagrm.2012.09.006. Epub 2012 Sep 21. PMID: 23000638 PMCID: PMC3552062

Cell Cycle and Cancer Biology Research Program, MS 48
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104

Phone: (405) 271-4570
Fax: (405) 271-7312
Jake-Kirkland@omrf.org

For media inquiries, please contact OMRF’s Office of Public Affairs at news@omrf.org.

Michaela Crossley
Research Technician II

Julia Skalka
Research Trainee

Adam Kulpa
Graduate Student

JinYoung Park
Graduate Student

Christian Wright
Graduate Student

Colter Bufford
Undergraduate Research Technician

Jase Daugherty
Administrative Assistant III

Denna Mills
Administrative Assistant III