Decreased Expression of CoREST1 and CoREST2 Together with LSD1 and HDAC1/2 during Neuronal Differentiation

Abstract

CoREST (CoREST1, rcor1) transcriptional corepressor together with the histone demethylase LSD1 (KDM1A) and the histone deacetylases HDAC1/2 form LSD1-CoREST-HDAC (LCH) transcriptional complexes to regulate gene expression. CoREST1 belong to a family that also comprises CoREST2 (rcor2) and CoREST3 (rcor3). CoREST1 represses the expression of neuronal genes during neuronal differentiation. However, the role of paralogs CoREST2 and CoREST3 in this process is just starting to emerge. Here, we report the expression of all CoRESTs and partners LSD1 and HDAC1/2 in two models of neuronal differentiation: Nerve-Growth-Factor (NGF)-induced neuronal phenotype of PC12 cells, and in vitro maturation of embryonic rat cortical neurons. In both models, a concomitant and gradual decrease of LSD1, HDAC1, HDAC2, CoREST1, and CoREST2, but not CoREST3 was observed. As required by the study, full-length rat rcor1 gene was identified using in silico analysis of available rat genome. The work was also complemented by the analysis of rat RNA-seq databases. The analysis showed that all CoRESTs, including the identified four splicing variants of rat CoREST3, display a wide expression in adult tissues. Moreover, the analysis of RNA-seq databases showed that CoREST2 displays a higher expression than CoREST1 and CoREST3 in the mature brain. Immunofluorescent assays and immunoblots of adult rat brain showed that all CoRESTs are present in both glia and neurons. Regarding functional partnership, CoREST2 and CoREST3 interact with all LSD1 splicing variants. In conclusion, neuronal differentiation is accompanied by decreased expression of all core components of LCH complexes, but not CoREST3. The combination of the differential transcriptional repressor capacity of LCH complexes and variable protein levels of its different components should result in a finely tuned gene expression during neuronal differentiation and in the adult brain.

KDM1A regulated the osteo/dentinogenic differentiation process of the stem cells of the apical papilla via binding with PLOD2

“…We then investigated the regulatory mechanism of KDM1A in SCAPs. KDM1A has been found to form protein complexes with other proteins during cell proliferation and differentiation . In the present study, we identified several candidate binding partners of KDM1A including PLOD2.…”

“…KDM1A has been found to form protein complexes with other proteins during cell proliferation and differentiation. [29][30][31] In the present study, we identified several candidate binding partners of KDM1A including PLOD2. Indeed, further study confirmed that KDM1A could bind with PLOD2 in SCAPs.…”

More than a Corepressor: The Role of CoREST Proteins in Neurodevelopment

“…Two paralogues, CoREST2 and CoREST3, have been found in humans and also form a complex with REST (McGann et al, 2014;Jung et al, 2018). However, their transcriptional activity and expression profile in the human brain remains largely unknown (Barrios et al, 2014;Sáez et al, 2015). Research suggests that each CoREST protein may play a different role in neurodevelopment via targeting unique genes in neural and glial cell types during development (Abrajano et al, 2009a(Abrajano et al, ,b, 2010.…”

CoRest1 regulates neurogenesis in a stage‐dependent manner

“…CoRest family members lack site‐specific DNA binding activity but associate with DNA through interactions with other proteins. CoRest1, together with lysine‐specific demethylase 1 (LSD1) and histone deacetylases (HDACs) 1/2, forms a powerful repressor known as the LSD1‐CoRest‐HDAC (LCH) complex . LSD1 binds to the second switching‐defective protein 3 (Swi3), adaptor 2 (Ada2), nuclear receptor co‐repressor (N‐CoR) and transcription factor (TF)IIIB (SANT) domain of CoRest and HDACs 1/2 bind to the Egl‐27 and MTA1 homology 2 (ELM2) and first SANT domain .…”

“…CoRest1, together with lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) 1/2, forms a powerful repressor known as the LSD1-CoRest-HDAC (LCH) complex. 15,16 LSD1 binds to the second switching-defective protein 3 (Swi3), adaptor 2 (Ada2), nuclear receptor co-repressor (N-CoR) and transcription factor (TF)IIIB (SANT) domain of CoRest and HDACs 1/2 bind to the Egl-27 and MTA1 homology 2 (ELM2) and first SANT domain. [17][18][19] LSD1 removes methyl groups from histone 3 at lysine 4 or 9 (H3K4/H3K9), 20 while HDACs remove acetyl groups from histone tails.…”