TitleArchitectural protein subclasses shape 3D organization of genomes during lineage commitment.
Publication TypeJournal Article
Year of Publication2013
AuthorsPhillips-Cremins, JE, Sauria, MEG, Sanyal, A, Gerasimova, TI, Lajoie, BR, Bell, JSK, Ong, C-T, Hookway, TA, Guo, C, Sun, Y, Bland, MJ, Wagstaff, W, Dalton, S, McDevitt, TC, Sen, R, Dekker, J, Taylor, J, Corces, VG
Date PublishedJune 2013
KeywordsAnimals, Cell Cycle Proteins, Cell Lineage, Chromatin, Chromosomal Proteins, Non-Histone, Embryonic Stem Cells, Enhancer Elements, Genetic, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Genome, Genome-Wide Association Study, Mediator Complex, Mice, Neural Stem Cells, Nuclear Proteins, Promoter Regions, Genetic, Repressor Proteins, Sequence Analysis, DNA

Understanding the topological configurations of chromatin may reveal valuable insights into how the genome and epigenome act in concert to control cell fate during development. Here, we generate high-resolution architecture maps across seven genomic loci in embryonic stem cells and neural progenitor cells. We observe a hierarchy of 3D interactions that undergo marked reorganization at the submegabase scale during differentiation. Distinct combinations of CCCTC-binding factor (CTCF), Mediator, and cohesin show widespread enrichment in chromatin interactions at different length scales. CTCF/cohesin anchor long-range constitutive interactions that might form the topological basis for invariant subdomains. Conversely, Mediator/cohesin bridge short-range enhancer-promoter interactions within and between larger subdomains. Knockdown of Smc1 or Med12 in embryonic stem cells results in disruption of spatial architecture and downregulation of genes found in cohesin-mediated interactions. We conclude that cell-type-specific chromatin organization occurs at the submegabase scale and that architectural proteins shape the genome in hierarchical length scales.

Alternate JournalCell
PubMed ID23706625
PubMed Central IDPMC3712340
Grant ListRC2HG005542 / HG / NHGRI NIH HHS / United States
R01HG003143 / HG / NHGRI NIH HHS / United States
R01GM035463 / GM / NIGMS NIH HHS / United States
R01DK065806 / DK / NIDDK NIH HHS / United States
R01 HG003143 / HG / NHGRI NIH HHS / United States
R01 GM035463 / GM / NIGMS NIH HHS / United States
P01GM85354 / GM / NIGMS NIH HHS / United States
5F32NS065603 / NS / NINDS NIH HHS / United States
T32 GM008490 / GM / NIGMS NIH HHS / United States