RRC ID 77256
Author Shang S, Li X, Azzo A, Truong T, Dozmorov M, Lyons C, Manna AK, Williams DC Jr, Ginder GD.
Title MBD2a-NuRD binds to the methylated γ-globin gene promoter and uniquely forms a complex required for silencing of HbF expression.
Journal Proc Natl Acad Sci U S A
Abstract During human development, there is a switch in the erythroid compartment at birth that results in silencing of expression of fetal hemoglobin (HbF). Reversal of this silencing has been shown to be effective in overcoming the pathophysiologic defect in sickle cell anemia. Among the many transcription factors and epigenetic effectors that are known to mediate HbF silencing, two of the most potent are BCL11A and MBD2-NuRD. In this report, we present direct evidence that MBD2-NuRD occupies the γ-globin gene promoter in adult erythroid cells and positions a nucleosome there that results in a closed chromatin conformation that prevents binding of the transcriptional activator, NF-Y. We show that the specific isoform, MBD2a, is required for the formation and stable occupancy of this repressor complex that includes BCL11A, MBD2a-NuRD, and the arginine methyltransferase, PRMT5. The methyl cytosine binding preference and the arginine-rich (GR) domain of MBD2a are required for high affinity binding to methylated γ-globin gene proximal promoter DNA sequences. Mutation of the methyl cytosine-binding domain (MBD) of MBD2 results in a variable but consistent loss of γ-globin gene silencing, in support of the importance of promoter methylation. The GR domain of MBD2a is also required for recruitment of PRMT5, which in turn results in placement of the repressive chromatin mark H3K8me2s at the promoter. These findings support a unified model that integrates the respective roles of BCL11A, MBD2a-NuRD, PRMT5, and DNA methylation in HbF silencing.
Volume 120(25)
Pages e2302254120
Published 2023-6-20
DOI 10.1073/pnas.2302254120
PMID 37307480
PMC PMC10288633
MeSH Adult Chromatin Cytosine DNA-Binding Proteins Fetal Hemoglobin* Genes, Regulator Humans Infant, Newborn Protein-Arginine N-Methyltransferases Transcription Factors gamma-Globins*
IF 9.412
Human and Animal Cells HUDEP-2(RCB4557)