Abstract
DNA methylation is an epigenetic mark that is essential for many biological processes and is linked to diseases such as cancer. Methylation is usually associated with transcriptional silencing, but new research has challenged this model. Both transcriptional activation and repression have recently been found to be associated with DNA methylation in a context-specific manner. How DNA methylation patterns are interpreted into different functional output remains poorly understood. One mechanism involves the protein ‘readers’ of methylation, which includes the methyl-CpG binding domain (MBD) family of proteins. This review examines the molecular and biological functions of MBD2, which binds to CpG methylation and is an integral part of the nucleosome remodeling and histone deacetylation (NuRD) complex. MBD2 has been linked to immune system function and tumorigenesis, yet little is known about its functions in vivo. Recent studies have found the MBD2 protein is ubiquitously expressed, with relatively high levels in the lung, liver, and colon. Mbd2 null mice surprisingly show relatively mild phenotypes compared to mice with loss of function of other MBD proteins. This evidence has previously been interpreted as functional redundancy between the MBD proteins. Here, we examine and contextualize research that suggests MBD2 has unique properties and functions among the MBD proteins. These functions translate to recently described roles in the development and differentiation of multiple cell lineages, including pluripotent stem cells and various cell types of the immune system, as well as in tumorigenesis. We also consider possible models for the dynamic interactions between MBD2 and NuRD in different tissues in vivo. The functions of MBD2 may have direct therapeutic implications for several areas of human disease, including autoimmune conditions and cancer, in addition to providing insights into the actions of NuRD and chromatin regulation.
Highlights
DNA Methylation and Its ReadersDNA methylation is a chemical epigenetic modification that is essential for mammalian viability and development
MCG at promoters is associated with transcriptional repression, while the same mark in gene bodies is associated with high levels of gene transcription (Schübeler, 2015)
It is clear that MBD2/nucleosome remodeling and histone deacetylation (NuRD) and MBD3/NuRD have distinct genome-wide distributions, reflecting their different DNA-binding properties, and different functions, in embryonic stem cells (ESCs) (Kaji et al, 2006; Gu et al, 2011; Baubec et al, 2013; Günther et al, 2013; Lu et al, 2014). Together these findings suggest that transcriptional regulation by MBD2 is more dynamic and multifaceted than originally proposed, and this may help explain why direct targets of MBD2 have been difficult to identify
Summary
DNA methylation is a chemical epigenetic modification that is essential for mammalian viability and development. DNA methylation, in the CpG context, is intimately linked to histone modifications, formation of heterochromatin, and transcription factor recruitment Together these mechanisms comprise the chromatin state and direct gene expression programs. There is evidence that these proteins are bound at actively transcribed genes in promoters or intragenic sites, the effect of this binding on transcriptional regulation is not fully understood (Baubec et al, 2013; Spruijt et al, 2013; Figures 1E,F) This and other new evidence shows that the MBD proteins are dynamic readers of methylation beyond their originally proposed roles as transcriptional repressors, and are essential to our understanding of epigenetic processes. Despite many biochemical and genetic studies on the MBD proteins, the precise functions of these proteins in vivo are yet to be fully investigated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
