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Title: Occupancy by key transcription factors is a more accurate predictor of enhancer activity than histone modifications or chromatin accessibility

Regulated gene expression controls organismal development, and variation in regulatory patterns has been implicated in complex traits. Thus accurate prediction of enhancers is important for further understanding of these processes. Genome-wide measurement of epigenetic features, such as histone modifications and occupancy by transcription factors, is improving enhancer predictions, but the contribution of these features to prediction accuracy is not known. Given the importance of the hematopoietic transcription factor TAL1 for erythroid gene activation, we predicted candidate enhancers based on genomic occupancy by TAL1 and measured their activity. Contributions of multiple features to enhancer prediction were evaluated based on the results of these and other studies. Results: TAL1-bound DNA segments were active enhancers at a high rate both in transient transfections of cultured cells (39 of 79, or 56%) and transgenic mice (43 of 66, or 65%). The level of binding signal for TAL1 or GATA1 did not help distinguish TAL1-bound DNA segments as active versus inactive enhancers, nor did the density of regulation-related histone modifications. A meta-analysis of results from this and other studies (273 tested predicted enhancers) showed that the presence of TAL1, GATA1, EP300, SMAD1, H3K4 methylation, H3K27ac, and CAGE tags at DNase hypersensitive sites gave the mostmore » accurate predictors of enhancer activity, with a success rate over 80% and a median threefold increase in activity. Chromatin accessibility assays and the histone modifications H3K4me1 and H3K27ac were sensitive for finding enhancers, but they have high false positive rates unless transcription factor occupancy is also included. Conclusions: Occupancy by key transcription factors such as TAL1, GATA1, SMAD1, and EP300, along with evidence of transcription, improves the accuracy of enhancer predictions based on epigenetic features.« less
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [3] ;  [1] ;  [1] ;  [4] ;  [1] ;  [5] ;  [5] ;  [6] ;  [3] ;  [1]
  1. Pennsylvania State Univ., University Park, PA (United States)
  2. Pennsylvania State Univ., University Park, PA (United States); Univ. of Michigan, Ann Arbor, MI (United States)
  3. The Children’s Hospital of Philadelphia, Philadelphia, PA (United States); Univ. of Pennsylvania, Philadelphia, PA (United States)
  4. Stanford University, Stanford, CA (United States)
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); DOE Joint Genome Institute, Walnut Creek, CA (United States)
  6. St Jude Children’s Research Hospital, Memphis, TN (US)
Publication Date:
OSTI Identifier:
1190586
Grant/Contract Number:
AC02-05CH11231
Type:
Accepted Manuscript
Journal Name:
Epigenetics & Chromatin
Additional Journal Information:
Journal Volume: 8; Journal Issue: 16; Journal ID: ISSN 1756-8935
Publisher:
BioMed Central
Research Org:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES functional genomics; gene regulation; TAL1; GATA1; histone modifications; enhancer assay