Chromodomain Helicase DNA-binding Family Research Articles

Comprehensive analysis of the expression, prognosis, and immune infiltrates for CHDs in human lung cancer

BackgroundThe chromodomain helicase DNA-binding (CHD) family, a group of genes that regulate nucleosome spacing and access to transcription factors, contributes to tumorigenesis in various cancers. However, the roles of CHD family members in lung cancer remain poorly understood.MethodsWe investigated the transcriptional, survival, and immune data of CHDs in patients with lung cancer from the Oncomine, UALCAN, GEPIA, Kaplan–Meier Plotter, TCGA, TIMER, cBioPortal, and CR2Cancer databases. Then, perform functional enrichment analysis of CHDs was performed using the Metascape. Finally, the expression of CHD7, CHD8 and DNA damage response genes were evaluated by quantitative real-time PCR and western blot.The effects of CHD7 or CHD8 knockdown on A549 and PC9 cells were measured in vitro by flow cytometry, cell viability and colony formation assays.ResultsWe found that except for CHD5, nearly all members of CHDs in lung cancer showed altered expression compared with adjacent normal tissues. Moreover, the abnormal expression levels of CHDs were related to the clinical outcome of patients with lung adenocarcinoma and, to a lesser extent, patients with lung squamous cell carcinoma, which were significantly associated with the immune infiltrating levels of immune cells. Furthermore, the functions of CHDs and their neighboring genes are mainly related to DNA repair, the cell cycle, and organelle organization. Finally, cellular experiments conducted in vitro confirmed that CHD7/8 played indispensable roles in DNA damage signaling and cell cycle progression in lung adenocarcinoma cells.ConclusionThis study implied that CHD family members, especially in subclass III, are potential targets of precision therapy and new biomarkers for patients with lung cancer.

Role of ATP-dependent chromatin remodelers in hematopoietic stem and progenitor cell maintenance.

ATP-dependent chromatin remodeling factors utilize energy from ATP hydrolysis to modulate DNA-histone structures and regulate gene transcription. They are essential during hematopoiesis and for hematopoietic stem and progenitor cell (HSPC) function. This review discusses the recently unveiled roles of these chromatin remodelers in HSPC regulation, with an emphasis on the mechanism of chromodomain helicase DNA-binding (CHD) family members. Recent studies of ATP-dependent chromatin remodelers have revealed that individual CHD family members engage in distinct mechanisms in regulating HSPC cell fate. For example, CHD8 is required for HSPC survival by restricting both P53 transcriptional activity and protein stability in steady state hematopoiesis while the related CHD7 physically interacts with RUNX family transcription factor 1 (RUNX1) and suppresses RUNX1-induced expansion of HSPCs during blood development. Moreover, other CHD subfamily members such as CHD1/CHD2 and CHD3/CHD4, as well as the switch/sucrose non-fermentable, imitation SWI, and SWI2/SNF2 related (SWR) families of chromatin modulators, have also been found important for HSPC maintenance by distinct mechanisms. The expanding knowledge of ATP-dependent chromatin remodelers in hematopoiesis illustrates their respective critical roles in HSPC maintenance including the regulation of HSPC differentiation, survival, and self-renewal. Further studies are warranted to elucidate how different chromatin remodeling complexes are integrated in various HSPC cell fate decisions during steady-state and stress hematopoiesis.

Chromatin Remodeling Proteins in Epilepsy: Lessons From CHD2-Associated Epilepsy.

The chromodomain helicase DNA-binding (CHD) family of proteins are ATP-dependent chromatin remodelers that contribute to the reorganization of chromatin structure and deposition of histone variants necessary to regulate gene expression. CHD proteins play an important role in neurodevelopment, as pathogenic variants in CHD1, CHD2, CHD4, CHD7 and CHD8 have been associated with a range of neurological phenotypes, including autism spectrum disorder (ASD), intellectual disability (ID) and epilepsy. Pathogenic variants in CHD2 are associated with developmental epileptic encephalopathy (DEE) in humans, however little is known about how these variants contribute to this disorder. Of the nine CHD family members, CHD2 is the only one that leads to a brain-restricted phenotype when disrupted in humans. This suggests that despite being expressed ubiquitously, CHD2 has a unique role in human brain development and function. In this review, we will discuss the phenotypic spectrum of patients with pathogenic variants in CHD2, current animal models of CHD2 deficiency, and the role of CHD2 in proliferation, neurogenesis, neuronal differentiation, chromatin remodeling and DNA-repair. We also consider how CHD2 depletion can affect each of these biological mechanisms and how these defects may underpin neurodevelopmental disorders including epilepsy.

Chromatin Remodeling in Development and Disease: Focus on CHD7

A central goal of developmental biology is to understand the mechanisms whereby undifferentiated, pluripotent cells differentiate into mature, organized cells and tissues. Recent advances in mouse genetics, embryonic stem cell manipulation, RNA inhibition, and genomics have now made it possible to explore these mechanisms with an unprecedented level of resolution. One major class of proteins, the chromodomain helicase DNA-binding (CHD) family of ATP-dependent chromatin remodelers, has emerged as important regulators of cellular differentiation. CHD proteins are thought to function in the nucleus via binding to DNA and regulating gene transcription. CHD7, a member of the CHD family, encodes a protein mutated in human CHARGE syndrome, a multiple anomaly disorder that affects hearing, vision, and cardiac, craniofacial, and nervous system development [1], [2]. Previous reports have shown tissue and developmental stage specific expression of CHD7 [3], [4], and there is evidence that CHD7 binds thousands of sites in the genome [5]. It is thus a major challenge to identify specific mechanisms of CHD7 action in pluripotency versus differentiation.

Expression and regulation of CReMM, a chromodomain helicase‐DNA‐binding (CHD), in marrow stroma derived osteoprogenitors

This study follows the expression of CReMM, a new CHD family member, in osteoprogenitors. CReMM expression was analyzed in primary cultured mesnchymal cells from rat and human. Analysis in ex vivo cultured marrow stromal cells (MSC) from rats revealed higher level of CReMM in cells from young (3 months), when compared to cells from old (15 months) rats. CReMM level was higher in human MSC then in mature trabecular bone cells (TBC). Within the MSC population, osteogenic clones showed higher levels of CReMM then non-osteogenic ones. We used bone marrow derived osteogenic cell line (MBA-15) to elaborate on the regulation of CReMM expression in correlation with cell proliferation and co-expression with alkaline phosphatase (ALK). CReMM is highly expressed in proliferating cells and is inversely related to expression of ALK. MBA-15 cells were challenged with dexamethasone (Dex) or 17beta-estradiol and quantification of CReMM at the protein (ELISA) and mRNA (RT-PCR) levels had shown that Dex upregulated CReMM levels. Since CReMM is regulated by Dex, we analyzed the interaction of CReMM with the glucocorticoid receptor (GR), which mediates Dex action. Co-immunopercipitation (Co-IP) demonstrated an association between CReMM and GR. In summary, CReMM is a CHD protein expressed by osteoprogenitors, and we suggest it plays a role in mediating transcriptional response to hormones that coordinate osteoblast function.