Overview. Research in the lab focuses on cellular and molecular mechanisms underlying cell and tissue aging, with emphasis on epigenetics and age-associated epigenetic changes that predispose to cancer. We are also interested in developing epigenetic therapies
Untitled to combat cancer, and ultimately epigenetic chemopreventative strategies. We employ in vitro
models, mouse models, human tissues and state-of-the-art analyses of large epigenomics and single cell sequencing datasets. We do collaborative, multidisciplinary research.

Why does the incidence of cancer increase with age? While we are fundamentally interested in basic mechanisms of cell and tissue aging, we are keen to understand how aging predisposes to disease. The incidence of many cancers increases with age. Indeed, age is the biggest single risk factor for many cancers. However, the reason for this is poorly understood (link to Cancer and Aging). We believe that a substantial reduction in the incidence and deaths from cancer will ultimately come from a better understanding of cancer as a disease of aging, thereby facilitating risk assessment, early detection and chemoprevention.


Figure : A model for age-associated increase in cancer incidence . Open lollipops, unmethylated CpG; filled lollipop, methylated CpG; yellow lightning bolt, genotoxic/mutagenic event.

Evidence suggests that multiple factors conspire to drive age-associated cancer (see Figure above). Some congenital cancer-causing mutations are thought to be well-tolerated by young cells and tissues (e.g. mutant gene B). Other cancer-causing mutations are acquired through aging (e.g. mutant gene A). These congenital and acquired mutations conspire with other more progressive events, telomere shortening, replication stress, epigenetic and metabolic changes, to drive a dramatic increase in late-life cancer. In the Adams lab, we are interested in defining the mechanistic causes and consequences of age-associated epigenetic changes, particularly those events that pre-dispose to cancer. A long-term goal of the lab is to develop epigenetic-based therapies that can prevent age-associated events that predispose to cancer, with a view to cancer chemoprevention.

See: Adams, P.D., Jasper, H., Rudolph, K.L., Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer. Cell Stem Cell, 2015 Jun 4;16(6):601-612. doi: 10.1016/j.stem.2015.05.002. PMID: 26046760



We have mapped the epigenetic landscape of senescent cells, and are defining the causes and consequences of this altered landscape. Cellular senescence is an irreversible proliferation arrest and pro-inflammatory phenotype triggered in primary cells by activated oncogenes and other molecular stresses. As a profound change in cell phenotype, the initiation and maintenance of senescence depends on reprogramming of chromatin, the epigenome and gene expression. Cellular senescence is a potent tumor suppressor mechanism. However, the accumulation of senescent cells with age also causes tissue aging, by blocking cell and tissue renewal and driving chronic inflammation. Indeed, in contrast to its acute tumor suppressive effects, chronic accumulation of inflammatory senescent cells is tumor promoting. In collaboration with Dr. Shelley Berger, we have mapped the distribution of several critical epigenetic regulators in proliferating and senescent cells, including DNA methylation, several histone modifications, histone variants and nuclear lamins. These collaborative studies have yielded critical insights into gene regulation in senescent cells (Cruickshanks et al., 2013; Rai et al., 2014; Shah et al., 2013), and the tumor suppressive and pro-aging effects of senescent cells (Cruickshanks et al., 2013; Nelson et al., 2016).

See: Cruickshanks, H.A., McBryan, T., Nelson, D.M., Vanderkraats, N.D., Shah, P.P., van Tuyn, J., . . . Adams, P.D. (2013) Senescent cells harbour features of the cancer epigenome. Nat Cell Biol 15, 1495-1506. PMCID: PMC4106249

Nelson, D.M., Jaber-Hijazi, F., Cole, J.J., Robertson, N.A., Pawlikowski, J.S., Norris, K.T., Criscione, S.W., Pchelintsev, N.A., Piscitello, D., Stong, N., Rai, T.S., McBryan, T., ……Adams, P.D. (2016) Mapping H4K20me3 onto the chromatin landscape of senescent cells indicates a function in control of cell senescence and tumor suppression. Genome Biol., 17(1), 158. doi: 10.1186/s13059-016-1017-x. PMCID: PMC4960804

Rai, T.S., Cole, J.J., Nelson, D.M., Dikovskaya, D., Faller, W.J., Vizioli, M.G., . . . Adams, P.D. (2014) HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia. Genes Dev 28, 2712-2725. PMCID: PMC4265675

Shah, P.P., Donahue, G., Otte, G.L., Capell, B.C., Nelson, D.M., Cao, K., . . . Adams*, P.D. Berger*, S.L. (2013). Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev 27, 1787-1799. * Co-corresponding authors. PMCID: PMC3759695

Landmark structure and functional studies on the HIRA histone chaperone complex and its role in senescence-mediated tumor suppression. In collaboration with Dr. Ronen Marmorstein in Philadelphia we have dissected the structure-function relationships between HIRA and its binding partners, UBN1, CABIN1 and ASF1a and substrate histone H3.3 (Zhang et al., 2005). This included a crystal structure of the HIRA/ASF1a interaction surface and more recently the UBN1/histone H3.3 interaction surface (Tang et al., 2006). We were the first to describe the distribution of the HIRA complex across the mammalian epigenome (Pchelintsev et al., 2013). In functional studies, we have demonstrated the role of this DNA replication independent histone chaperone complex in the control of chromatin in non-proliferating senescent cells (Rai et al., 2014). These studies have been facilitated by the mouse monoclonal and rabbit polyclonal antibodies that we have made to all subunits of the complex. More recently, we have generated the first conditional knock out mice of HIRA, UBN1 and CABIN1 and are using these to establish in vivo functions (Rai et al., 2014). Of particular note, we have revealed a function for HIRA in promoting healthy aging and the suppression of cancer (Rai et al., 2014).

See: Zhang, R., Poustovoitov, M.V., Ye, X., Santos, H.A., Chen, W., Daganzo, S.M., . . . Adams, P.D. (2005) Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell 8, 19-30.

Tang, Y., Poustovoitov, M.V., Zhao, K., Garfinkel, M., Canutescu, A., Dunbrack, R., . . . Adams*, P.D., Marmorstein*, R. (2006) Structure of a human ASF1a-HIRA complex and insights into specificity of histone chaperone complex assembly. Nat Struct Mol Biol 13, 921-929. Co-corresponding authors.

Pchelintsev, N.A., McBryan, T., Rai, T.S., van Tuyn, J., Ray-Gallet, D., Almouzni, G., and Adams, P.D. (2013). Placing the HIRA histone chaperone complex in the chromatin landscape. Cell Rep 3, 1012-1019. PMCID: PMC3974909

Rai, T.S., Cole, J.J., Nelson, D.M., Dikovskaya, D., Faller, W.J., Vizioli, M.G., . . . Adams, P.D. (2014). HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia. Genes Dev 28, 2712-2725. PMCID: PMC4265675

We coined the term “chromostasis” to describe the presumptive homeostatic mechanisms that confer epigenetic stability over the lifecourse, and we were major contributors to the first demonstration of a DNA methylation clock in the mouse. Maintenance of cell phenotype and suppression of disease, including cancer, over the lifecourse depends on a high level of epigenetic stability. However, since chromatin is inherently dynamic (Rai et al., 2014), this steady state stability likely reflects a challenge for the cell. Therefore, presumptive “chromatin homeostasis” or “chromostasis” mechanisms are predicted to actively maintain an epigenetic steady state over the lifecourse, thereby suppressing age-associated disease (Rai et al., 2014). We have shown that histone chaperone HIRA is one such factor that contributes to epigenetic stability in non-proliferating cells (Ye et al., 2007). Recently, we reported the first DNA methylation clock in the mouse, and showed that diverse interventions – genetic, dietary and drug – that promote longevity of mice also suppress age-associated epigenetic changes and slow progression of this DNA methylation “clock”, i.e. enhance chromostasis (Cole et al., 2017; Wang et al., 2017).

See: Rai, T.S., Cole, J.J., Nelson, D.M., Dikovskaya, D., Faller, W.J., Vizioli, M.G., . . . Adams, P.D. (2014) HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia. Genes Dev 28, 2712-2725. PMCID: PMC4265675

Zhang, R., Poustovoitov, M.V., Ye, X., Santos, H.A., Chen, W., Daganzo, S.M., . . . Adams, P.D. (2005) Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell 8, 19-30.

Cole, J.J., Robertson, N.A., Rather, M.I., Thomson, J.P., McBryan, T. Sproul, D. Wang, T. Brock, C; Clark, W., Ideker, T. Meehan, R.R. Miller, R.A., Brown-Borg, H., Adams, P.D. (2017) Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions. Genome Biology. PMCID: PMC5370462

Wang, T., Tsui, B., Kreisberg, J.F., Robertson, N.A., Gross, A.M., Carter, H., Brown-Borg, H., Adams, P.D, Ideker, T. (2017) Epigenetic aging signatures in mice are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biology. PMCID: PMC5371228

We have demonstrated a “tug of war” between tumor suppressive oncogene-induced senescence and oncogenic activated Wnt signaling in melanocytic neoplasia (Adams and Enders, 2008; Ye et al., 2007). The balance between these tumor suppressive and oncogenic activities determines the efficiency of senescence-mediated tumor suppression. For example, we showed that in oncogene-expressing melanocytes a low level of activated Wnt signaling promotes benign nevus formation (Pawlikowski et al., 2013). However, a high level of activated Wnt signaling, caused by germline sequence variants, promotes giant congenital nevi in the form of congenital melanocytic nevus (CMN) syndrome (Pawlikowski et al., 2015). In a mouse model that closely recapitulates the human genetics, we showed that activated Wnt signaling and an activated Ras oncogene (NRasQ61K) cooperate to drive CMN syndrome, and that this is suppressed by acute post-natal treatment with MEK inhibitors (Pawlikowski et al., 2015). Based on these studies, our collaborator Dr. Veronica Kinsler is preparing to test MEK inhibitors in babies afflicted by CMN syndrome.

See: Ye, X., Zerlanko, B., Kennedy, A., Banumathy, G., Zhang, R., and Adams, P.D. (2007) Downregulation of Wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells. Mol Cell 27, 183-196.

Pawlikowski, J.S., Brock, C., Chen, S.C., Al-Olabi, L., Nixon, C., McGregor, F., . . . Adams, P.D. (2015) Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling. J Invest Dermatol 135, 2093-2101. PMCID: PMC4539947

Pawlikowski, J.S., McBryan, T., van Tuyn, J., Drotar, M.E., Hewitt, R.N., Maier, A.B., . . . Adams, P.D. (2013) Wnt signaling potentiates nevogenesis. Proc Natl Acad Sci U S A 110, 16009-16014. PMCID: PMC3791768

Adams, P.D., and Enders, G.H. (2008) Wnt signaling and senescence: A tug of war in early neoplasia? Cancer Biol Ther 7. PMCID: PMC2783518

We first characterized Cytoplasmic Chromatin Fragments (CCF) in senescent cells and in collaboration defined a role for CCF as drivers of inflammation via the cGAS/STING cytoplasmic DNA sensing anti-viral pathway. Cellular senescence is a potent tumor suppressor mechanism by virtue of proliferation arrest and the senescence associated secretory phenotype (SASP) which promotes clearance of pre-malignant cells by the immune system. However, the mechanism responsible for initiation of SASP has been unknown. In 2013, our lab first characterized and named CCF as fragments of chromatin expelled from the nucleus of senescent cells into the cytoplasm. Then, in 2015, in collaboration with Shelley Berger’s laboratory, we showed that the formation of CCF depends on the interaction between lamin B1 and autophagy adaptor LC3 in the nucleus, and that lamin B1 is a nuclear substrate of autophagy. Most recently, again with Shelley Berger’s lab, we have shown that CCF are sensed by the cytoplasmic DNA sensing anti-viral apparatus, cGAS and STING, and that this leads to activation of NFκB and SASP in senescent cells. The role of CCF as triggers of SASP, via cGAS and STING, has been confirmed by several other labs.

See: Ivanov, A., Pawlikowski, J., Manoharan, I., van Tuyn, J., Nelson, D. M., Rai, T. S., Shah, P. P., Drotar, M., Wu, H., Berger, S. L., and Adams, P. D. (2013) Lysosome-dependent processing of histones in senescent cells. J. Cell Biol., 202:129-43. doi: 10.1083/jcb.201212110.

Dou, Z., Capell, BC., Drake, AM., Shah, PP., Dorsey, J., Simola, D., Donahue, G., Zhu, Z., Sammons, M., Rai, TS., Natale, C., Ridky, T., Goldman, R., Adams, PD., Berger, SL. (2015) Autophagy mediates degradation of nuclear lamina. Nature, 527:105-9. doi: 10.1038/nature15548. Epub 2015 Oct 28.

Dou, D., 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., Ahasan Al Tanim, KM., Barber, GN., Seykora, JT., Millar, SE., Kaestner, KH., Garcia, BA., Adams, PD.*, Berger, SL*. (2017) Cytoplasmic chromatin triggers inflammation in senescence and cancer. * Corresponding authors. Nature, In press










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