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Published April 13, 2012 | Accepted Version + Supplemental Material
Journal Article Open

Dynamic Transformations of Genome-wide Epigenetic Marking and Transcriptional Control Establish T Cell Identity


T cell development comprises a stepwise process of commitment from a multipotent precursor. To define molecular mechanisms controlling this progression, we probed five stages spanning the commitment process using RNA-seq and ChIP-seq to track genome-wide shifts in transcription, cohorts of active transcription factor genes, histone modifications at diverse classes of cis-regulatory elements, and binding repertoire of GATA-3 and PU.1, transcription factors with complementary roles in T cell development. The results highlight potential promoter-distal cis-regulatory elements in play and reveal both activation sites and diverse mechanisms of repression that silence genes used in alternative lineages. Histone marking is dynamic and reversible, and though permissive marks anticipate, repressive marks often lag behind changes in transcription. In vivo binding of PU.1 and GATA-3 relative to epigenetic marking reveals distinctive factor-specific rules for recruitment of these crucial transcription factors to different subsets of their potential sites, dependent on dose and developmental context.

Additional Information

© 2012 Elsevier Inc. Received 9 August 2011. Revised 29 November 2011. Accepted 26 January 2012. Available online 12 April 2012. Published: April 12, 2012. We thank Lorian Schaeffer and Vijaya Kumar for library preparation and sequencing, Henry Amrhein and Diane Trout for data curation, Igor Antoshechkin for sequencing facility management, Diana Perez, Josh Verceles, and Rochelle Diamond for cell sorting and advice, Tian Ling, Georgi Marinov, and Hao Yuan Kueh for statistical advice and programming, Rothenberg group members for sharing advice and unpublished data, and Robert Butler, Lorena Sandoval, and Scott Washburn for care of the mice. Support was from NIH grants R33HL089123, R01CA090233, R01CA090233-08S1, and RC2CA148278, the Beckman Institute, the Millard and Muriel Jacobs Genetics and Genomics Center, the L.A. Garfinkle Memorial Laboratory Fund, the Al Sherman Foundation, the Bren Professorship (B.J.W.), and the A.B. Ruddock Professorship (E.V.R.).

Attached Files

Accepted Version - nihms364557.pdf

Supplemental Material - DocumentS1.pdf

Supplemental Material - TableS1.xls

Supplemental Material - TableS2.xls

Supplemental Material - TableS3.xls

Supplemental Material - TableS4.xls

Supplemental Material - TableS5.xls

Supplemental Material - TableS6.xls

Supplemental Material - TableS7.xml


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