De novo DNA demethylation and non-coding transcription define active intergenic regulatory elements

Schlesinger, F., Smith, A. D., Gingeras, T. R., Hannon, G. J., Hodges, E. (2013) De novo DNA demethylation and non-coding transcription define active intergenic regulatory elements. Genome Research, 23 (10). pp. 1601-1614. ISSN 10889051 (ISSN)

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URL: http://www.ncbi.nlm.nih.gov/pubmed/23811145
DOI: 10.1101/gr.157271.113

Abstract

Deep sequencing of mammalian DNA methylomes has uncovered a previously unpredicted number of discrete hypomethylated regions in intergenic space (iHMRs). Here, we combined whole genome bisulfite sequencing data with extensive gene-expression and chromatin-state data to define functional classes of iHMRs, and to reconstruct the dynamics of their establishment in a developmental setting. Comparing HMR profiles in embryonic stem and primary blood cells, we show that iHMRs mark an exclusive subset of active DNase hypersensitive sites (DHS), and that both developmentally constitutive and cell-type specific iHMRs display chromatin states typical of distinct regulatory elements. We also observe that iHMR changes are more predictive of nearby gene activity than the promoter HMR itself, and that expression of non-coding RNAs within the iHMR accompanies full activation and complete demethylation of mature B cell enhancers. Conserved sequence features corresponding to iHMR transcript start sites, including a discernable TATAA motif, suggest a conserved, functional role for transcription in these regions. Similarly, we explored both primate-specific and human-population variation at iHMRs, finding that while enhancer iHMRs are more variable in sequence and methylation status than any other functional class, conservation of the TATA box is highly predictive of iHMR maintenance, reflecting the impact of sequence plasticity and transcriptional signals on iHMR establishment. Overall, our analysis allowed us to construct a 3-step timeline in which 1) intergenic DHS are pre-established in the stem cell, 2) partial demethylation of blood specific intergenic DHSs occurs in blood progenitors, and 3) complete iHMR formation and transcription coincide with enhancer activation in lymphoid-specified cells.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA methylation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL labs > Gingeras lab
CSHL labs > Hannon lab
Watson School > Publications
CSHL Cancer Center Shared Resources > Bioinformatics Service
Depositing User: Matt Covey
Date Deposited: 18 Jul 2013 14:53
Last Modified: 03 Nov 2015 16:08
PMCID: PMC3787258
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28452

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