The histone demethylase Lsd1 regulates multiple repressive gene programs during T cell development

2021 ◽  
Vol 218 (12) ◽  
Author(s):  
Daniel B. Stamos ◽  
Lauren M. Clubb ◽  
Apratim Mitra ◽  
Laura B. Chopp ◽  
Jia Nie ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Histone Demethylase ◽  
Interferon Response ◽  
Gene Promoters ◽  
Critical Function ◽  
Gene Signatures ◽  
Transcriptional Changes ◽  
Cell Gene

Analysis of the transcriptional profiles of developing thymocytes has shown that T lineage commitment is associated with loss of stem cell and early progenitor gene signatures and the acquisition of T cell gene signatures. Less well understood are the epigenetic alterations that accompany or enable these transcriptional changes. Here, we show that the histone demethylase Lsd1 (Kdm1a) performs a key role in extinguishing stem/progenitor transcriptional programs in addition to key repressive gene programs during thymocyte maturation. Deletion of Lsd1 caused a block in late T cell development and resulted in overexpression of interferon response genes as well as genes regulated by the Gfi1, Bcl6, and, most prominently, Bcl11b transcriptional repressors in CD4+CD8+ thymocytes. Transcriptional overexpression in Lsd1-deficient thymocytes was not always associated with increased H3K4 trimethylation at gene promoters, indicating that Lsd1 indirectly affects the expression of many genes. Together, these results identify a critical function for Lsd1 in the epigenetic regulation of multiple repressive gene signatures during T cell development.

scholarly journals ATP-dependent chromatin remodeling in T cells1This article is part of Special Issue entitled Asilomar Chromatin and has undergone the Journal’s usual peer review process.

2012 ◽  
Vol 90 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Andrea L. Wurster ◽  
Michael J. Pazin
Keyword(s):  
Gene Regulation ◽  
T Cell ◽  
Cell Fate ◽  
Chromatin Remodeling ◽  
Peer Review Process ◽  
T Cell Development ◽  
Cell Development ◽  
Compare And Contrast ◽  
Cell Gene ◽  
Present Understanding

One of the best studied systems for mammalian chromatin remodeling is transcriptional regulation during T cell development. The variety of these studies have led to important findings in T cell gene regulation and cell fate determination. Importantly, these findings have also advanced our knowledge of the function of remodeling enzymes in mammalian gene regulation. First we briefly present biochemical and cell-free analysis of 3 types of ATP dependent remodeling enzymes (SWI/SNF, Mi2, and ISWI) to construct an intellectual framework to understand how these enzymes might be working. Second, we compare and contrast the function of these enzymes during early (thymic) and late (peripheral) T cell development. Finally, we examine some of the gaps in our present understanding.

scholarly journals Knock-in Mutation of the Distal Four Tyrosines of Linker for Activation of T Cells Blocks Murine T Cell Development

2001 ◽  
Vol 194 (2) ◽  
pp. 135-142 ◽  
Author(s):  
Connie L. Sommers ◽  
Rashmi K. Menon ◽  
Alexander Grinberg ◽  
Weiguo Zhang ◽  
Lawrence E. Samelson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Effector Proteins ◽  
Regulatory Sequences ◽  
Thymocyte Development ◽  
Critical Function ◽  
Tyrosine Residues

The integral membrane adapter protein linker for activation of T cells (LAT) performs a critical function in T cell antigen receptor (TCR) signal transduction by coupling the TCR to downstream signaling pathways. After TCR engagement, LAT is tyrosine phosphorylated by ZAP-70 creating docking sites for multiple src homology 2–containing effector proteins. In the Jurkat T cell line, the distal four tyrosines of LAT bind PLCγ-1, Grb2, and Gads. Mutation of these four tyrosine residues to phenylalanine (4YF) blocked TCR-mediated calcium mobilization, Erk activation, and nuclear factor (NF)-AT activation. In this study, we examined whether these four tyrosine residues were essential for T cell development by generating LAT “knock-in” mutant mice that express the 4YF mutant protein under the control of endogenous LAT regulatory sequences. Significantly, the phenotype of 4YF knock-in mice was identical to LAT−/− (null) mice; thymocyte development was arrested at the immature CD4−CD8− stage and no mature T cells were present. Knock-in mice expressing wild-type LAT protein, generated by a similar strategy, displayed a normal T cell developmental profile. These results demonstrate that the distal four tyrosine residues of LAT are essential for preTCR signaling and T cell development in vivo.

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