Brian C. Capell, M.D., Ph.D.
421 Curie Boulevard
1020-21 BRB II/III
Philadelphia, PA 19104
Epithelial tissues rely on a highly coordinated balance between self-renewal, proliferation, and differentiation. Epigenetic mechanisms provide this precise control through the regulation of gene enhancer and transcriptional networks that establish and maintain cell fate and identity. Disruption of these pathways can lead to a loss of proliferative control, ultimately driving cancer.
Consistent with this, chromatin regulators are amongst the most frequently mutated genes in all of cancer, with an exceptionally high incidence of mutations in cancers of self-renewing epithelial tissues, such as squamous cell carcinoma (SCC). SCC is the most common type of cancer worldwide, affecting numerous epithelial tissues ranging from the skin and eyes to the lung, esophagus, and oropharynx. Despite this, precisely how disruption of epigenetic homeostasis may drive epithelial cancers such as SCC is poorly understood.
In the Capell Lab, we combine cutting-edge epigenetic technologies, human patient samples, primary cells, and mouse models in order to solve several fundamental unanswered questions:
- How is the skin epigenome altered by intrinsic (i.e. aging) and extrinsic (i.e. ultraviolet radiation) environmental influences, and how do these changes contribute to disease?
- How do chromatin regulatory enzymes function in both normal and diseased skin, particularly during carcinogenesis?
- Can we target the epigenome with precision to treat disease?
Through this, we hope to identify new epigenetic targets for prevention and treatment of these potentially deadly cancers.
Contribution to Science
Demonstrated the importance of the KMT2D-LSD1-H3K4 methylation axis in epithelial homeostasis:Epithelial tissues rely on a highly coordinated balance between self-renewal, proliferation and differentiation; disruption of which may drive carcinogenesis. Here we established the first known role of the epigenetic regulatorKMT2D (MLL4) in epithelial enhancer control, including the regulation of p63-target genes involved in epithelial development, differentiation and stratification. Additionally, we have now shown that LSD1 serves to oppose the role of KMT2D by repressing major fate-determining transcription factors that drive epithelial differentiation and may serve as an effective therapeutic target for cutaneous squamous cell carcinoma.
- Lin-Shiao E, Lan Y, Coradin M, Anderson A, Donahue G, Simpson CL, Sen P, Saffie R, Busino L, Garcia BA, Berger SL, Capell BC. “KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis.” Genes Dev.32(2): 2018. PMID: 29440247
- Egolf S, Aubert Y, Doepner M, Anderson A, Maldonado-Lopez A, Pacella G, Lan Y, Simpson CL, Ridky T, Capell BC. “LSD1 inhibition promotes epithelial differentiation through derepression of fate-determining transcription factors.” Cell Reports. 28(8): 2019. PMID: 31433976
- Aubert Y, Egolf S, Capell BC. “The Unexpected Noncatalytic Roles of Histone Modifiers in Development and Disease.” Trends in Genetics. 35(9): 2019. PMID: 31301850
- Egolf S, Capell BC. “LSD1: a viable therapeutic target in cutaneous squamous cell carcinoma?” Expert Opin Ther Targets. Online ahead of print: 2020. PMID: 32379508
Demonstrated the role of MLL1 and chromatin alterations in senescence and DNA damage-induced inflammation: We have shown that senescent cells possess large-scale alterations in the epigenome (Shah, et al. 2013; Dou, et al. 2015), and that MLL1, a known H3K4me3 methyltransferase and oncogene, is critical for the expression of DNA-damage response (DDR)-induced inflammation (Capell, et al. 2016), also known as the senescence-associated secretory phenotype (SASP) in the context of senescence (Ghosh and Capell, et al. 2016). MLL1 inhibition can dramatically attenuate the expression and secretion of the SASP, and ameliorate the pro-carcinogenic effects of the SASP, while having no effects on the expression of tumor suppressors or the senescence growth arrest. Together this work suggests that epigenetic abnormalities in senescence can be targeted to prevent its pro-cancer and pro-aging effects.
- Shah PP, Donahue G, Otte G, Capell BC, Nelson DM, Cao K, Aggarwala V, Cruickshanks HA, Singh Rai T, McBryan T, Gregory BD, Adams PD, Berger SL. “Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and in the chromatin landscape” Genes Dev. 27(16): 2013. PMID: 23934658
- Dou Z, Xu C, Donahue G, Ivanov A, Pan J, Zhu J, Capell BC, Catanzaro JM, Ricketts MD, Shimi T, Adam SA, Mamorstein R, Zong WX, Goldman RD, Johansen T, Adams PD, Berger SL. “Autophagy mediates degradation of nuclear lamina.” Nature. 527(7576): 2015. PMID: 26524528
- Capell BC, Drake A, Shah PP, Dorsey J, Simola DF, Dou Z, Zhu J, Sammons M, Donahue G, Singh Rai T, Natale C, Ridky TW, Adams PD, Berger SL. “MLL1 epigenetically regulates expression of ATM and the senescence-associated secretory phenotype” Genes Dev. 30(3): 2016. PMID: 26833731
- Dou Z, Ghosh K, Vizioli MG, Zhu J, Sen P, Wangensteen KJ, Simithy J, Lan Y, Lin Y, Zhou Z, Capell BC, Xu C, Xu M, Kieckhaefer JE, Jiang T, Shoshkes-Carmel M, Tanim KM, Barber G, Seykora JT, Millar SE, Kaestner KH, Garcia BA, Adams PD, Berger SL. “Cytoplasmic chromatin triggers inflammation in senescence and cancer”. Nature. 550(7676): 2017. PMID: 28976970
Established farnesyltransferase inhibitors as a potential therapy for Hutchinson-Gilford progeria syndrome (HGPS): We have demonstrated both in vitro and in vivo that farnesyltransferase inhbitors (FTIs) are efficacious in improving phenotypes in model systems of the most dramatic form of human premature aging, HGPS. This work was proof of principle that FTIs may be effective for the cardiovascular disease which is the major cause of mortality in HGPS. This work has been replicated by numerous other labs, and FTIs have now been shown to improve patient phenotypes in the very first clinical trial of human HGPS patients, providing the first therapeutic option for these patients.
- Capell BC, Erdos MR, Madigan JP, Fiordalisi JJ, Varga R, Conneely KN, Gordon LB, Der CJ, Cox AD, Collins FS. “Inhibiting the farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome”. Proc Natl Acad Sci USA. 102(36): 2005. PMID: 16129833
- Varga R, Eriksson M, Erdos MR, Olive M, Harten I, Kolodgie F, Capell BC, Cheng J, Faddah D, Perkins S, Avallone H, San H, Qu X, Ganesh S, Gordon LB, Virmani R, Wight TN, Nabel EG, Collins FS. “Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson-Gilford progeria syndrome”. Proc Natl Acad Sci USA. 103(9): 2006. PMID: 16492728
- “Farnesyltransferase inhibitors for treatment of laminopathies, cellular aging and atherosclerosis.” Filed with the United States Patent and Trademark Office, European Patent Office, international patent number: 06733984.6-2123-US2006002977 (USPTO#: 20080131375 – Class: 424 92 USPTO). Publication Number: WO/2006/081444 with the World Intellectual Property Organization: 2007.
- Capell BC, Olive M, Erdos MR, Cao K, Faddah DA, Whipperman M, San H, Qu X, Ganesh SK, Chen X, Avallone H, Kolodgie F, Virmani R, Nabel EG, Collins FS. “A farnesyltransferase inhibitor prevents the onset and late progression of cardiovascular disease in a progeria mouse model”. Proc Natl Acad Sci USA. 105(41): 2008. PMID: 18838683
Demonstrated links between mechanisms of premature aging in Hutchinson-Gilford progeria syndrome (HGPS) and the normal human aging process: We have shown that in normal human aging, cells also produce small but increasing amounts of the mutant protein, progerin, which directly causes premature aging in HGPS. These increases in progerin lead to abnormalities in nuclear architecture with aging in both HGPS and normal cells. Furthermore, we have demonstrated that variations in the LMNA gene, which when mutated can cause HGPS as well as other diseases of premature aging, may in fact serve a protective function, as a particular form (haplotype) of this gene was overrepresented in centenarian populations.
- Cao K, Capell BC, Erdos MR, Djabali K, Collins FS. “A lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in both progeria and normal cells”. Proc Natl Acad Sci USA. 104(12): 2007. PMID: 17360355
- Capell BC, Collins FS. “Human laminopathies: nuclei gone genetically awry”. Nat Rev Genet. 7(12): 2006. PMID: 17139325
- Capell BC, Tlougan BE, Orlow SJ. “From the rarest to the most common: insights from progeroid syndromes into skin cancer and aging.” J Invest Dermatol. 129(10): 2009. PMID: 19387478
- Conneely KN, Capell BC, Erdos MR, Sebastiani P, Timofeev N, Terry DF, Baldwin CT, Budagov T, Atzmon G, Barzalai N, Thomas GA, Puca AA, Perls TT, Geesaman BJ, Boehnke M, Collins FS. “Human longevity and common variations in the LMNA gene: a meta-analysis.” Aging Cell. 11(3): 2012. PMID: 22340368
|FIRST NAME||LAST NAME||TITLE|
|Yann||Aubert||Post Doc Fellowfirstname.lastname@example.org|
|Amy||Anderson||Lab Manager/Research Specialistemail@example.com|
|Eun Kyung||Ko||Postdoc Fellow||EunKyung.Ko@pennmedicine.upenn.edu|