Epigenetic inheritance of transcriptional programs is essential for cell proliferation, cell differentiation and malignant transformation. Molecularly, epigenetic inheritance of transcriptional programs relies in large part on conservation of chromatin structure through disruptive cell cycle phases. Despite the biological importance of this phenomenon, the details of the molecular mechanisms of epigenetic inheritance are elusive, mostly because of the lack of appropriate experimental approaches. We developed new experimental paradigms, and found that many chromosomal proteins are associated with DNA during replication. However, methylated histones are accumulated on nascent DNA with significant delay. Our preliminary results suggest that following DNA replication, undifferentiated cells, including mouse embryonic stem cells (mESCs), accumulate methylated histones and resume transcription more slowly than differentiated cells of the same origin. We hypothesize that this may create a narrow time window at the time of DNA replication, with a uniquely open chromatin configuration lacking histone modifications and lacking transcription that is very susceptible to receiving signals for differentiation. We will test this hypothesis by examining th accumulation of different modified histone residues, histone-modifying and chromatin remodeling proteins following DNA replication during differentiation of mouse ESCs. We will also examine when transcription resumes in these cells, and when components of the transcriptional machinery are recruited to nascent DNA. Finally, we will test a hypothesis that the short period of time just after DNA replication, when chromatin is not modified, provides a window of opportunity for acquiring signals for differentiation through association of the newly induced transcription factors. This may account for a higher plasticity of undifferentiated states in acquiring new transcriptional programs. Overall, this proposal will greatly contribute to the ke epigenetic issues during cell differentiation.

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Development is accompanied by gradual differentiation of embryonic or progenitor cells into the somatic cells of the adults. The mechanisms responsible for maintaining cell identity and for cell differentiation rely on epigenetic inheritance of the gee activation and repression programs. We propose to investigate key questions concerning molecular mechanisms of these processes, and the results of these studies will greatly benefit our understanding of fundamental biological and health related issues.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Development - 2 Study Section (DEV2)
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Carter, Anthony D
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Thomas Jefferson University
Schools of Medicine
United States
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Petruk, Svetlana; Cai, Jingli; Sussman, Robyn et al. (2017) Delayed Accumulation of H3K27me3 on Nascent DNA Is Essential for Recruitment of Transcription Factors at Early Stages of Stem Cell Differentiation. Mol Cell 66:247-257.e5
Akishina, Angelina A; Vorontsova, Julia E; Cherezov, Roman O et al. (2017) Xenobiotic-induced activation of human aryl hydrocarbon receptor target genes in Drosophila is mediated by the epigenetic chromatin modifiers. Oncotarget 8:102934-102947
Petruk, Svetlana; Mariani, Samanta A; De Dominici, Marco et al. (2017) Structure of Nascent Chromatin Is Essential for Hematopoietic Lineage Specification. Cell Rep 19:295-306
Petruk, Svetlana; Fenstermaker, Tyler K; Black, Kathryn L et al. (2016) Detection of RNA-DNA association by a proximity ligation-based method. Sci Rep 6:27313
L Black, Kathryn; Petruk, Svetlana; Fenstermaker, Tyler K et al. (2016) Chromatin proteins and RNA are associated with DNA during all phases of mitosis. Cell Discov 2:16038
Petruk, Svetlana; Black, Kathryn L; Kovermann, Sina K et al. (2013) Stepwise histone modifications are mediated by multiple enzymes that rapidly associate with nascent DNA during replication. Nat Commun 4:2841
Petruk, Svetlana; Sedkov, Yurii; Johnston, Danika M et al. (2012) TrxG and PcG proteins but not methylated histones remain associated with DNA through replication. Cell 150:922-33
Orlovsky, Kira; Kalinkovich, Alexander; Rozovskaia, Tanya et al. (2011) Down-regulation of homeobox genes MEIS1 and HOXA in MLL-rearranged acute leukemia impairs engraftment and reduces proliferation. Proc Natl Acad Sci U S A 108:7956-61
Johnston, Danika M; Sedkov, Yurii; Petruk, Svetlana et al. (2011) Ecdysone- and NO-mediated gene regulation by competing EcR/Usp and E75A nuclear receptors during Drosophila development. Mol Cell 44:51-61
Petruk, Svetlana; Smith, Sheryl T; Sedkov, Yurii et al. (2008) Association of trxG and PcG proteins with the bxd maintenance element depends on transcriptional activity. Development 135:2383-90

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