The broad, long term goal of the proposed study is to determine, at the molecular level, mechanisms and function of ATP-dependent chromatin remodeling in vivo. ATP-dependent chromatin remodeling factors are highly conserved ATPases that utilize the energy of ATP hydrolysis to alter chromatin structure. Because of their biochemical activities and high abundance, ATP-dependent chromatin remodeling factors can affect a wide variety of DNA- dependent processes, including transcription, DNA replication and DNA damage repair. The importance of physiological roles the chromatin remodeling factors play are highlighted by the fact that many of them are mutated in a variety of human diseases, including cancer. Therefore, elucidating the mechanisms and functions of chromatin remodeling factors will significantly impact not only basic sciences but also medical sciences. In the current funding cycle of this grant, we have made surprising discovery that chromatin remodeling factors regulate transcription of non-coding RNA (ncRNA) and activity of the S phase checkpoint. It has recently become clear that a significant fraction of eukaryotic genomes are transcribed to produce ncRNA. Some of them play critical roles in controlling cell differentiation, gene expression, and cancer development. However, physiological roles of the vast majority of ncRNA are unknown. Moreover, mechanisms to regulate ncRNA transcription are almost entirely unknown. The S phase checkpoint plays essential roles in the maintenance of genome stability. However, how its activity is regulated is not well understood. We will take advantage of our recent findings that highly conserved chromatin remodeling factors regulate ncRNA and the S phase checkpoint activity, and elucidate the underlying mechanisms and biological functions of these regulatory mechanisms.

Public Health Relevance

The S phase checkpoint and non-coding RNA transcripts play critical roles in normal cell growth and their mis-regulation can lead to serious diseases such as cancer. However, how they are regulated remains largely unknown. The goal of our work is to understand the molecular mechanisms by which the S phase checkpoint and non-coding RNA transcription are precisely controlled.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-GGG-C (02))
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Carter, Anthony D
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Fred Hutchinson Cancer Research Center
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McKnight, Jeffrey N; Tsukiyama, Toshio; Bowman, Gregory D (2016) Sequence-targeted nucleosome sliding in vivo by a hybrid Chd1 chromatin remodeler. Genome Res 26:693-704
Alcid, Eric A; Tsukiyama, Toshio (2016) Expansion of antisense lncRNA transcriptomes in budding yeast species since the loss of RNAi. Nat Struct Mol Biol 23:450-5
Alcid, Eric A; Tsukiyama, Toshio (2016) Systematic approaches to identify functional lncRNAs. Curr Opin Genet Dev 37:46-50
Lee, Laura; Rodriguez, Jairo; Tsukiyama, Toshio (2015) Chromatin remodeling factors Isw2 and Ino80 regulate checkpoint activity and chromatin structure in S phase. Genetics 199:1077-91
Alcid, Eric A; Tsukiyama, Toshio (2014) ATP-dependent chromatin remodeling shapes the long noncoding RNA landscape. Genes Dev 28:2348-60
Rodriguez, Jairo; McKnight, Jeffrey N; Tsukiyama, Toshio (2014) Genome-Wide Analysis of Nucleosome Positions, Occupancy, and Accessibility in Yeast: Nucleosome Mapping, High-Resolution Histone ChIP, and NCAM. Curr Protoc Mol Biol 108:21.28.1-16
Rodriguez, Jairo; Tsukiyama, Toshio (2013) ATR-like kinase Mec1 facilitates both chromatin accessibility at DNA replication forks and replication fork progression during replication stress. Genes Dev 27:74-86
Yadon, Adam N; Singh, Badri Nath; Hampsey, Michael et al. (2013) DNA looping facilitates targeting of a chromatin remodeling enzyme. Mol Cell 50:93-103
Yadon, Adam N; Tsukiyama, Toshio (2013) DNA looping-dependent targeting of a chromatin remodeling factor. Cell Cycle 12:1809-10
Yadon, Adam N; Tsukiyama, Toshio (2011) SnapShot: Chromatin remodeling: ISWI. Cell 144:453-453.e1

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