Interplay between cofactors and transcription factors in hematopoiesis and hematological malignancies

Abstract

Hematopoiesis requires finely tuned regulation of gene expression at each stage of development. The regulation of gene transcription involves not only individual transcription factors (TFs) but also transcription complexes (TCs) composed of transcription factor(s) and multisubunit cofactors. In their normal compositions, TCs orchestrate lineage-specific patterns of gene expression and ensure the production of the correct proportions of individual cell lineages during hematopoiesis. The integration of posttranslational and conformational modifications in the chromatin landscape, nucleosomes, histones and interacting components via the cofactor–TF interplay is critical to optimal TF activity. Mutations or translocations of cofactor genes are expected to alter cofactor–TF interactions, which may be causative for the pathogenesis of various hematologic disorders. Blocking TF oncogenic activity in hematologic disorders through targeting cofactors in aberrant complexes has been an exciting therapeutic strategy. In this review, we summarize the current knowledge regarding the models and functions of cofactor–TF interplay in physiological hematopoiesis and highlight their implications in the etiology of hematological malignancies. This review presents a deep insight into the physiological and pathological implications of transcription machinery in the blood system.

4.1N-Mediated Interactions and Functions in Nerve System and Cancer

“…The 4.1N is correlated with tumor progression, aggressive behaviors in NSCLC and EOC, and chemotherapy resistance in EOC. 4.1N is also related to liver disease ( Stepanova et al, 2010 ), cardiac disease ( JBirks et al, 2003 ; Taylor-Harris et al, 2005 ; Pinder et al, 2012 ), nonsyndromic intellectual disability ( Hamdan et al, 2011 ), hereditary Parkinson’s disease ( Auburger et al, 2019 ), and reproductive system disease ( Wang et al, 2020b ; Wang et al, 2021 ). The FERM and CTD represent two adaptors where a number of regulations converge on the association of protein 4.1N with its partners, through which 4.1N locates, supports, and coordinates partners in signaling transduction.…”

EP400NL is required for cMyc-mediated PD-L1 gene activation by forming a transcriptional coactivator complex

“…Although cMyc level was not altered significantly by the serum stimulation in our EP400NL inducible Flp-In™ T-REx™ cells, serum stimulation in the presence of upregulated EP400NL appears to enhance the Myc binding to the PD-L1 promoter. ChIP data shows that the recruitment of EP400NL to the target promoter requires the binding of DNA binding transcription factors such as cMyc or other unknown serum-stimulated factors at the promoter (52). The co-immunoprecipitation studies of cMyc and EP400NL complex and their enrichment at the Myc binding site of PD-L1 gene support our model that cMyc recruits epigenetic modifying complexes to remodel the target gene promoters for transcriptional activation (Figure 8).…”

Clearing the Haze: How Does Nicotine Affect Hematopoiesis before and after Birth?

“…Several key regulators of hematopoiesis have been identified and characterized in detail. Transcription factors such as Runx1, SCL, Gata-2, and C-myb play key roles in the intrinsic regulation of HSC potential during development [ 20 , 27 , 28 ]. Additionally, inflammatory regulators like interferons, interleukin (IL)-1, IL-6, and TNFα provide HSC-extrinsic cues to regulate HSC fate choice and function [ 29 , 30 , 31 , 32 ].…”