The chromatin remodeler Mi-2beta is required for CD4 expression and T cell development.
Changes in chromatin structure underlie the activation or silencing of genes during development. The chromatin remodeler Mi-2beta is highly expressed in thymocytes and is presumed to be a transcriptional repressor because of its presence in the nucleosome remodeling deacetylase (NuRD) complex. Using conditional inactivation, we show that Mi-2beta is required at several steps during T cell development: for differentiation of beta selected immature thymocytes, for developmental expression of CD4, and for cell divisions in mature T cells. We further show that Mi-2beta plays a direct role in promoting CD4 gene expression. Mi-2beta associates with the CD4 enhancer as well as the E box binding protein HEB and the histone acetyltransferase (HAT) p300, enabling their recruitment to the CD4 enhancer and causing histone H3-hyperacetylation to this regulatory region. These findings provide important insights into the regulation of CD4 expression during T cell development and define a role for Mi-2beta in gene activation.
Williams
Christine J
CJ
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Naito
Taku
T
Arco
Pablo Gómez-Del
PG
Seavitt
John R
JR
Cashman
Susan M
SM
De Souza
Beverly
B
Qi
Xiaoqing
X
Keables
Piper
P
Von Andrian
Ulrich H
UH
Georgopoulos
Katia
K
D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins; D015704:CD4 Antigens / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases / Q000378:metabolism; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D019076:Transgenes / Q000235:genetics; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D051792:Basic Helix-Loop-Helix Proteins; D015704:CD4 Antigens; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C489532:Tcf12 protein, mouse