Distinct properties of cell-type-specific and shared transcription factor binding sites.
Most human transcription factors bind a small subset of potential genomic sites and often use different subsets in different cell types. To identify mechanisms that govern cell-type-specific transcription factor binding, we used an integrative approach to study estrogen receptor α (ER). We found that ER exhibits two distinct modes of binding. Shared sites, bound in multiple cell types, are characterized by high-affinity estrogen response elements (EREs), inaccessible chromatin, and a lack of DNA methylation, while cell-specific sites are characterized by a lack of EREs, co-occurrence with other transcription factors, and cell-type-specific chromatin accessibility and DNA methylation. These observations enabled accurate quantitative models of ER binding that suggest tethering of ER to one-third of cell-specific sites. The distinct properties of cell-specific binding were also observed with glucocorticoid receptor and for ER in primary mouse tissues, representing an elegant genomic encoding scheme for generating cell-type-specific gene regulation.
HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA.
Jason
J
Gertz
Daniel
D
Savic
Katherine E
KE
Varley
E Christopher
EC
Partridge
Alexias
A
Safi
Preti
P
Jain
Gregory M
GM
Cooper
Timothy E
TE
Reddy
Gregory E
GE
Crawford
Richard M
RM
Myers
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D017124:Conserved Sequence; D019175:DNA Methylation; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008954:Models, Biological; D011401:Promoter Regions, Genetic / Q000187:drug effects; D034622:RNA Interference; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D013816:Thermodynamics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D004958:Estradiol