MEF2C and EBF1 Co-regulate B Cell-Specific Transcription.

Nikki R Kong,Matthew Davis,Astar Winoto,Robert Tjian,Li Chai,H Leighton Grimes

doi:10.1371/journal.pgen.1005845

Abstract

Hematopoietic stem cells are capable of self-renewal or differentiation along three main lineages: myeloid, erythroid, and lymphoid. One of the earliest lineage decisions for blood progenitor cells is whether to adopt the lymphoid or myeloid fate. Previous work had shown that myocyte enhancer factor 2C (MEF2C) is indispensable for the lymphoid fate decision, yet the specific mechanism of action remained unclear. Here, we have identified early B cell factor-1 (EBF1) as a co-regulator of gene expression with MEF2C. A genome-wide survey of MEF2C and EBF1 binding sites identified a subset of B cell-specific genes that they target. We also determined that the p38 MAPK pathway activates MEF2C to drive B cell differentiation. Mef2c knockout mice showed reduced B lymphoid-specific gene expression as well as increased myeloid gene expression, consistent with MEF2C’s role as a lineage fate regulator. This is further supported by interaction between MEF2C and the histone deacetylase, HDAC7, revealing a likely mechanism to repress the myeloid transcription program. This study thus elucidates both activation and repression mechanisms, identifies regulatory partners, and downstream targets by which MEF2C regulates lymphoid-specific differentiation.

Highlights

Hematopoiesis is the process that generates all blood cell types throughout the lifetime of an animal
Despite the characterization of many transcription factors and their functions in B cell differentiation, there still remains an incomplete understanding of how these molecules work together and the hierarchy involved in cell lineage determination
It had been shown in skeletal muscle cells that Myocyte enhancer factor 2C (MEF2C) can interact with basic helix-loop-helix transcription factors such as Myogenin [20]

Summary

Introduction

Hematopoiesis is the process that generates all blood cell types throughout the lifetime of an animal. CCAAT/enhancer binding protein alpha (C/EBPα) (GenBank EDL03027.1) acts as the “master” myeloid regulator [3] [4], and E2A proteins—E12 (UniProt E9PWE2) and E47 (UniProt E9PVV2) isoforms—function as key transcription factors for the lymphoid fates [5,6]. They do not display B cell-specific expression, E2A proteins are known to activate important B lineage transcription factors such as early B cell factor-1 (EBF1) [7,8]. Myocyte enhancer factor 2C (MEF2C) was a likely candidate to drive this process

Methods

Results

Discussion

Conclusion