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A Functional Role for REST Co-Repressor 2 (Rcor2) in Callosal Development

ABSTRACT: Pallial functional organization is mediated by the dynamic interplay of a broad spectrum of cellular and molecular cues that promote midline patterning, neurogenesis, axon guidance and neural connectivity. The regulators that orchestrate these seminal processes are still poorly understood. By employing a pallial conditional ablation model, we report that the transcriptional and epigenetic modulator, REST corepressor 2 (Rcor2) plays key roles in organizing the developing corticoseptal boundary. ChIP-seq and RNA-seq analyses reveal that Rcor2 modulates a diverse repertoire of classes of genes with essential roles in CC development, including pallial/subpallial patterning, cell fate specification and axon guidance.

ORGANISM(S): Mus musculus

PROVIDER: GSE118751 | GEO | 2020/05/01

REPOSITORIES: GEO

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Project description:CoREST complexes, composed of LSD1, HDAC1/2, and RCoR1/2/3, are pivotal in neurodevelopment and have long been recognized as transcriptional repressors across various cancers. However, distinct roles of the three RCoR factors remain underexplored. Here, we unveil non-canonical functions of RCoR2 in MYCN-amplified neuroblastoma (NB), underscoring its unique significance compared to its paralogues. This novel insight shifts the paradigm, highlighting RCoR2 as a key determinant of NB chromatin landscape.NB cell growth and tumorigenesis critically depend on RCoR1 and 2, with the RCOR2 gene exhibiting high histone acetylation levels and selective increased expression in NB. Unlike the well-known repressive roles of RCoR1, RNA-seq analyses demonstrate RCoR2 as a positive regulator of gene expression. RCoR2 predominantly occupies active promoters and regions of open chromatin marked by H3K27ac and Pol2, defining its distinct binding pattern compared to RCoR1, which primarily targets enhancers. Surprisingly, CoREST complexes co-occupy chromatin with NB core regulatory transcription factors (CRTFs), which positively drive NB-specific signatures. RCoR2, and not RCoR1, interacts with CRTFs, regulates their expression and its transcription is activated through a strong Super-enhancer. Collectively, these data indicate RCoR2 as a new component of the adrenergic NB core regulatory circuitry (CRC). Mechanistically, H3K27ac and H3K4me2 levels are not drastically altered upon RCoR2 reduction, suggesting RCoR2 is not the primary driver of CoREST complexes’ catalytic activity. Instead, HiChIP data indicate that RCoR2 mediates chromatin looping, facilitating enhancer-promoter interactions and maintaining 3D chromatin architecture to sustain oncogenic transcriptional programs. Taken together, our data underscore RCoR2 as a key oncogenic determinant in neuroblastoma due to its role in chromatin landscape. We propose a model in which RCoR2 facilitates interactions between CRTF-bound enhancers and their associated transcription start sites, thereby sustaining the expression of genes essential for neuroblastoma survival. Consequently, we reveal RCoR2 as a novel critical vulnerability in high-risk neuroblastoma and a promising target for cancer therapeutics.

Project description:Epigenetic regulation of bone formation is a complex network of active proteins and their cofactors. Recent developments in calcified tissue research have revealed several important pathways of epigenetic regulation leading to transcriptional changes in bone cells. Rest Corepressor 2 (Rcor2) is a coregulator of Lysine-specific histone demethylase 1 (Lsd1), a demethylase linked to osteoblast activity, hematopoietic stem cell differentiation and malignancy of different neoplasms. However, the role of Rcor2 in osteoblast differentiation has not yet been examined in detail. We have previously shown that Rcor2 is highly expressed in mesenchymal stromal cells (MSC) and particularly in the osteoblastic lineage. The role of Rcor2 in osteoblastic differentiation in vitro was further characterized and we demonstrate here that lentiviral silencing of Rcor2 in MC3T3-E1 cells led to a decrease in osteoblast differentiation, as shown by decreased alkaline phosphatase and von Kossa stainings as well as by decreased expression of several osteoblast-related marker genes. RNA-sequencing of the Rcor2-downregulated MC3T3-E1 cells revealed decreased repression of Rcor2 target genes, as well as significant upregulation of majority of the differentially expressed genes. While the heterozygous, global loss of Rcor2 in vivo did not lead to a detectable bone phenotype, conditional deletion of Rcor2 in limb-bud mesenchymal cells led to a moderate decrease in cortical bone volume, which was not accentuated by challenging bone formation by ovariectomy or tibial fracture. Furthermore, a global deletion of Rcor2 led to decreased amount of white adipose tissue in vivo and decreased the capacity of primary cells to differentiate into adipocytes in vitro, while the conditional deletion led to decreased adiposity in fracture calluses. Taken together, these results suggest that epigenetic regulation of mesenchymal stromal cell differentiation is mediated by Rcor2, which could thus play an important role in defining the MSC fate.

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A Functional Role for REST Co-Repressor 2 (Rcor2) in Callosal Development

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