Following Francis Collins emphasis on intramural-extramural collaborations and the application of cutting-edge tools to research, the NIH Mouse Regulome Project was established in 2010. The primary objective of this program is to elucidate how gene expression is regulated in the mouse genome by combining the latest technology developed at intramural and extramural NIH labs. At each stage of the project different extramural investigators are invited to participate.
Stage I: 2010-2013
Participating Laboratories:
David Levens (NCI), Keji Zhao (NHLBI), Lino Tesarrollo (NCI), Teresa Przyticka (NLM), Jan Hoeijmakers and Wim Vermeulen (Erasmus Medical Center, the Netherlands).
Objectives and main findings:
Using ES and B cells we uncovered a new phenomenon we called transcriptome amplification, whereby the entire transcriptional program of G0 cells is augmented ~10-fold as they enter the cell cycle. Myc and the TFIIH complex play a key role in this process.
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Stage II: 2013-2014
Participating Laboratories:
Yijun Ruan (Jackson labs), Gordon Hager (NCI), Keith Joung (Harvard), Michel Nussenzweig (Rockefeller), Qiang Pan-Hammarstrom (Karolinska Institute), and Fred Alt (Harvard).
Objectives and main findings:
Using 3C technology we showed that as cells differentiate during embryonic development, promoters for some broadly expressed genes (e.g. Pim1, Myc) become tethered to a completely different set of enhancers, demonstrating that the DNA regulatory landscape of mammalian cells is highly dynamic.
Another finding was that the B cell deaminase AID, responsible for recombination and hypermutation of Ig genes, is promiscuously recruited by highly interactive super-enhancer domains, a feature that helps explain why lymphocytes are particularly prone to chromosomal translocations and tumor development.
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Stage III: 2014-2017
Participating Laboratories:
Erez Lieberman Aiden (Baylor), Andre Nussenzweig (NCI), Yijun Ruan (Jackson labs), Gordon Hager (NCI), Lino Tessarrollo (NCI), Monique Floer (Michigan), Melike Lakadamyali (Barcelona), Hari Schroff (NIBIB), Zhe Liu (Janelia Farm, HHMI).
Objectives and main findings:
These studies revealed that the genome of naïve B lymphocytes is poised. Namely, that RNA PolII, TFs, chromatin remodeling complexes, histone acetyltransferases, methyltransferases, and nuclear architectural proteins, are preloaded in G0 chromatin. Their activity however is maintained at basal levels until their catalytic substrates or cofactors reach an optimal concentration upon antigen encounter.
On another set of studies we showed that the activities behind nuclear architecture in B and other cell types render the genome vulnerable to topoisomerase-induced DNA breaks. We also found evidence that these lesions become substrates for chromosomal translocations in human cancer.
Our studies have also defined a new architectural feature we dubbed "stripes" which primarily tether super-enhancers to cognate promoters and facilitates Ig gene transcription and recombination.
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Stage IV: 2018-present
Participating Laboratories:
Erez Lieberman Aiden (Baylor), Yijun Ruan (Jackson labs), Francisco Asturias (UC Denver), Fred Alt (Harvard), Anshul Kundaje (Stanford), and Felipe Cortes Ledesma (Seville).