Mbd2-CP2c loop drives adult-type globin gene expression and definitive erythropoiesis

Abstract

During hematopoiesis, red blood cells originate from the hematopoietic stem cell reservoir. Although the regulation of erythropoiesis and globin expression has been intensively investigated, the underlining mechanisms are not fully understood, including the interplay between transcription factors and epigenetic factors. Here, we uncover that the Mbd2-free NuRD chromatin remodeling complex potentiates erythroid differentiation of proerythroblasts via managing functions of the CP2c complexes. We found that both Mbd2 and Mbd3 expression is downregulated during differentiation of MEL cells in vitro and in normal erythropoiesis in mouse bone marrow, and Mbd2 downregulation is crucial for erythropoiesis. In uninduced MEL cells, the Mbd2-NuRD complex is recruited to the promoter via Gata1/Fog1, and, via direct binding through p66α, it acts as a transcriptional inhibitor of the CP2c complexes, preventing their DNA binding and promoting degradation of the CP2c family proteins to suppress globin gene expression. Conversely, during erythropoiesis in vitro and in vivo, the Mbd2-free NuRD does not dissociate from the chromatin and acts as a transcriptional coactivator aiding the recruitment of the CP2c complexes to chromatin, and thereby leading to the induction of the active hemoglobin synthesis and erythroid differentiation. Our study highlights the regulation of erythroid differentiation by the Mbd2-CP2c loop.

Rational discovery of antimetastatic agents targeting the intrinsically disordered region of MBD2

“…Therefore, targeting MBD2 specifically at its IDPR would be a promising approach to the development of antimetastatic agents by inhibiting its DOT-based PPI with p66α that is essential for the integration of CRC and thus for its critical function in EMT. In addition, no noticeable adverse effects displayed by MBD2 inhibitors can be expected from the fact that down-regulation of MBD2 expression is essential for normal cell differentiation ( 33 ), and yet, MBD2 knockout ( MBD2 −/− ) mice exhibit normal survival and reproduction ( 34 ).…”

Development of a MEL Cell-Derived Allograft Mouse Model for Cancer Research

“…Regarding employment of MEL cells as a cellular model of erythropoiesis [7,8,9,10,11,12,13,14,15,16,17], we successfully confirmed that Mbd2 and p66α have different roles in erythroid differentiation and tumorigenicity in vivo (Figure 2). Therefore, our MEL cell-transfused allograft model provides a valuable tool to discriminate between erythroid differentiation and tumorigenic potential of erythroleukemia by examining splenomegaly and circulating cells in the blood.…”

“…We found earlier that the Mi-2/nucleosome remodeling deacetylase (NuRD) chromatin remodeling complex (CRC) potentiates erythroid differentiation of proerythroblasts by regulating functions of the CP2c complex [7]. CP2c (also known as TFCP2, CP2, α-CP2, LSF, and LBP-1c) is a ubiquitously expressed transcription factor [8,9,10], exerting a critical role in globin expression and erythropoiesis [11,12,13,14].…”

“…The proper CRC assembly is critically mediated by the MBD2-p66α interaction [16,17]. Both Mbd2 and Mbd3 expression is down-regulated during differentiation of MEL cells in vitro and in normal erythropoiesis in mouse bone marrow, and Mbd2, but not Mbd3, down-regulation is crucial for erythropoiesis [7]. On the other hand, arbitral modulation of Mbd2 expression, but not those of Mbd3 or p66α, or inhibition of Mbd2-p66α interaction by the p66αΔ1 peptide induced both α- and β-globin expression and functional hemoglobin synthesis (about 25% of the normal differentiated MEL cells) by benzidine staining at the undifferentiated state [7], suggesting that MBD2-free NuRD functions as transcriptional coactivator for proper erythroid differentiation, while disruption of MBD2–NuRD by dissociation of the NuRD integrator p66α, does not induce functional hemoglobin synthesis at the undifferentiated state.…”

Regulating the Regulators: The Role of Histone Deacetylase 1 (HDAC1) in Erythropoiesis

“…Notably, the NuRD complex become MBD2 free during erythropoiesis. Therefore, the complex that acts as a transcriptional coactivator may have different configurations to facilitate gene activation [ 85 ].…”