Jacob G. Kirkland, Ph.D.

Chromatin Regulators in Cancer Lab

In my lab we study how alterations in certain genes drive cancer. Many people know that a mutation in an important gene can lead to cancer, but another cause can be when a cell turns on a gene that is supposed to be off or turns off a gene that should be on. Similarly, there are two copies of each gene in our cells, but some cancers have more or fewer copies. Breast cancer, in particular, shows these latter features rather than high mutation rates. My lab will study a particular class of genes called Chromatin Regulators that control which genes get turned on or off in a cell and when genes are turned on, how much they are turned on. Chromatin Regulators are altered in up to 50% of cancer patients making them one of the most altered classes of genes.

A second issue in cancer is that some cancers have common alterations in certain genes, whereas other cancers rarely or never have alterations in these same genes. My lab will solve this fundamental challenge in biology of understanding why some genes are altered in some particular cancers but not in others.

Together, these findings will allow us to better predict which therapies will benefit each individual patient, harnessing the power or genetic/chemical synergy, allowing for more a personalized medicine approach.

Topo Inhibitor Sensitivity & Breast Cancer Transcriptional Networks

The accessibility of the genome to regulatory, recombination and repair proteins is controlled in part by the opposition between trithorax and polycomb genes that fine-tune accessibility, histone modifications and gene activity. Breast cancer is largely driven by copy-number variation (CNV) and altered gene dosage. What leads to CNV in breast cancer is largely unknown, but CNV may result from structural and organizational changes in the nucleus as a result of altered chromatin regulation. To determine chromatin regulators that may contribute to this phenomenon I collaborated with the lab of Christina Curtis recently published at Nature Medicine. I specifically served as the bridge between the dry and wet lab portions of this study and performed all wet lab experiments. Our results indicate that CRGs operate within a breast cancer specific co-variance transcriptional network that includes members of the classic polycomb and trithorax genes but broadly extends to over 100 chromatin regulators. To validate the extensive chromatin regulatory network, we used a systems biology approach with the aim of achieving a better understanding of chromatin regulator modulation of anthracycline response in breast cancer patients. Since anthracyclines work in part via inhibition of topoisomerase-II (TOP2) on accessible DNA, I hypothesized that CRGs that mediate DNA accessibility might predict anthracycline response. Using cell line datasets and evaluating the interaction between CRG expression and treatment in predicting survival in a metacohort of early-stage breast cancer patients, I identify CRGs whose expression levels dictate anthracycline benefit across the clinical subgroups. Consistent with my hypothesis, CRGs that promote DNA accessibility,including trithorax complex members, were associated with anthracycline sensitivity when highly expressed, whereas CRGs that reduce accessibility were associated with decreased anthracycline sensitivity. Using molecular biology approaches I validated that expression levels of a CR, KDM4B, modulates TOP2 accessibility to chromatin, elucidating a new pathway of anthracycline resistance. Our novel data-driven methodology identifies a collection of chromatin regulatory genes that form a cancer specific covariate network, parts of which predict response to TOP2 inhibitors likely through alteration of chromatin accessibility. This chromatin regulatory network will inform a robust signature of anthracycline (TOP2i) response that is broadly applicable and provides insight for novel therapeutic targeting and with implications for breast cancer patient stratification and treatment decisions.

Epigenome Editing with FIRE-dCas9

The mSWI/SNF complexes are mutated in 20% of tumors making them one of the most mutated CR complexes in cancer4. In the past, the mechanism of action of ATP-dependent chromatin regulators, such as mSWI/SNF was largely explored using in vitro methods based on measurements of nucleosome mobility.  These studies were limited by the fact that these assays were not sensitive to tissue-specific chromatin modifications, topology, long-range interactions, and complex patterns of histone modifications as well as patterns of DNA methylation and human disease mutational backgrounds. To circumvent these problems, I developed the FIRE-Cas9 system that allows one to recruit a specific chromatin regulator and follow the consequences with minute-by-minute kinetics on physiologic chromatin, which I published as a co-first author in Nature Communications. I can examine any locus of biologic or medical importance in virtually any cell type using this technique. Because CR complexes have alterations in many human cancers, it is imperative to understand the mechanism of action of these complexes with unparalleled precision as a basis for therapeutic development. The FIRE-Cas9 system that I developed allows one to do this for the first time.

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

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

View more publications

Recent Publications

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

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

Karol Tchorz
Research Trainee

JinYoung Park
Graduate Student

Cheryl "Cheri" Rutledge
Administrative Assistant III

Denna Mills
Administrative Assistant II