The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression program to control neurite outgrowth

Abstract

The mitotic deacetylase complex (MiDAC) is a recently identified histone deacetylase (HDAC) complex. While other HDAC complexes have been implicated in neurogenesis, the physiological role of MiDAC remains unknown. Here, we show that MiDAC constitutes an important regulator of neural differentiation. We demonstrate that MiDAC functions as a modulator of a neurodevelopmental gene expression program and binds to important regulators of neurite outgrowth. MiDAC upregulates gene expression of pro-neural genes such as those encoding the secreted ligands SLIT3 and NETRIN1 (NTN1) by a mechanism suggestive of H4K20ac removal on promoters and enhancers. Conversely, MiDAC inhibits gene expression by reducing H3K27ac on promoter-proximal and -distal elements of negative regulators of neurogenesis. Furthermore, loss of MiDAC results in neurite outgrowth defects that can be rescued by supplementation with SLIT3 and/or NTN1. These findings indicate a crucial role for MiDAC in regulating the ligands of the SLIT3 and NTN1 signaling axes to ensure the proper integrity of neurite development.

PROSER1 mediates TET2 O-GlcNAcylation to regulate DNA demethylation on UTX-dependent enhancers and CpG islands

“…RNA was finally eluted in 50 μl H 2 O and concentration determined with a NanoDrop 8000 Spectrophotometer. The following RNA quantification, quality check, strand-specific library preparation, and sequencing were performed by the Hartwell Center at St. Jude Children's Research Hospital as previously described (Mondal et al, 2020).…”

“…DNA from all inputs and supernatants was purified using the QIAquick PCR Purification Kit (28106; QIAGEN). DNA quantification, quality check, library preparation and sequencing were performed by the Hartwell Center at St. Jude Children's Research Hospital as previously described (Mondal et al, 2020).…”

ZFP541 is indispensable for pachytene progression by interacting with KCTD19 and activates meiotic gene expression in mouse spermatogenesis

“…HDAC1/2 complex is conventionally thought of as a genome-wide transcriptional repressor via histone deacetylation (Hassig et al, 1997; Kadosh and Struhl, 1998; Lee et al, 2018; Xue et al, 1998). In recent years, there have been many studies that HDAC1/2 tend to localize to transcriptionally active loci including promoters, gene bodies and enhancers (Jacob et al, 2011; Mondal et al, 2020; Wang et al, 2009). HDAC1/2 activity and targeting to specific gene loci strongly depends on the complexes they are involved in (Kelly and Cowley, 2013; Millard et al, 2017).…”

“…ZFP541, also known as SHIP1, has been previously identified in the spermatocyte UniGene library, which displays testis-specific expression (Choi et al, 2008). ZFP541 contains five zinc finger motifs that bind to DNA, and an ELM2-SANT domain which recruits and activates HDAC1/2 (Choi et al, 2008; Mondal et al, 2020). Choi et al .…”

Structure-Based Inhibitor Discovery of Class I Histone Deacetylases (HDACs)

“…The MiDAC complex contains HDAC1/2, DNTTIP1 (deoxynucleotidyl-transferase terminal-interacting protein 1) and the mitotic deacetylase-associated SANT domain (MIDEAS) corepressor protein [ 15 ], playing regulatory roles in gene expression of neuronal and embryonic development [ 88 , 89 ]. A previous study suggested that MiDAC is a tetrameric complex that contains four copies of HDAC1/2, DNTTIP1 and MIDEAS, respectively [ 90 ].…”