PgmNr M5042:
Downregulation of MBD2, a Mi-2/NuRD Chromatin Remodeling Complex Component, Potentiates Erythroid Terminal Differentiation and Hemoglobin Synthesis by Allowing the DNA Binding of CP2c TF Complexes.

Authors:
Chul Geun Kim 1 ; Min Young Kim 1 ; Ji Sook Kim 1 ; Hea Young Eum 1 ; Dae Hyun Ha 1 ; Seung Han Son 1 ; Mi-Ae Park 1 ; Yea Woon Kim 2 ; Eun Jung Baek 3 ; AeRi Kim 2 ; Ji Hyung Chae 1


Institutes
1) Hanyang University, Seoul, KR; 2) Pusan National University, Pusan, KR; 3) Hanyang University, Guri-si, KR.


Abstract:

Regulation of erythropoiesis and globin gene expression had been intensively investigated, as an effort to improve the management of common but devastating genetic hemoglobinopathies, leading to breakthroughs for the understanding of regulation of eukaryotic gene expression. A heterohexameric ternary transcription factor (TF) complex of TFCP2 (CP2c), CYP27B1 (CP2b), and PIAS1 (CBP) binds to the α-globin promoter to induce transcriptional activation of α-globin in erythroid cells (Kang et al., Nucleic Acids res, 2010), while CP2c homotetramer is known to charge in most cases. We found that GATAD2A (p66α), a component of the Mi-2/NuRD chromatin remodeling complex (CRC), interacts with CP2c/CP2b per se and represses CBP-mediated α-globin expression by modulating both their DNA binding and cellular protein levels. Interestingly, the p66α protein level was not changed during erythroid differentiation in vitro and in vivo and, instead, MBD2/MBD3, other components of the Mi-2/NuRD CRC and known to directly interact with p66α, was dramatically reduced in their expression: the transcriptional activity of CBP is inversely correlated with expression levels of MBD2 and MBD3. We have studied how the interplay between CP2c TF complexes and Mi-2/NuRD members potentiates terminal erythropoiesis and globin gene expression using multi-disciplinary tools of methods, and found that MBD2/3 directly regulates p66α function to CP2c TF complexes and thus downregulation of MBD2 potentiates erythroid terminal differentiation and hemoglobin synthesis by allowing the DNA binding of CP2c TF complexes. Our findings open up a new mode of CRC action on transcriptional regulation in general and a molecular execution mechanism of erythropoiesis at the terminal stage by interplay between CRC and TFs, leading to transcriptional induction of globin gene expression.