Abstract
BackgroundNeural tube defects (NTDs) are common birth defects involving the central nervous system. Recent studies on the etiology of human NTDs have raised the possibility that epigenetic regulation could be involved in determining susceptibility to them.ResultsHere, we show that the H2AK119ub1 E3 ligase CUL4B is required for the activation of retinoic acid (RA)-inducible developmentally critical homeobox (HOX) genes in NT2/D1 embryonal carcinoma cells. RA treatment led to attenuation of H2AK119ub1 due to decrease in CUL4B, further affecting HOX gene regulation. Furthermore, we found that CUL4B interacted directly with RORγ and negatively regulated its transcriptional activity. Interestingly, knockdown of RORγ decreased the expression of HOX genes along with increased H2AK119ub1 occupancy levels, at HOX gene sites in N2/D1 cells. In addition, upregulation of HOX genes was observed along with lower levels of CUL4B-mediated H2AK119ub1 in both mouse and human anencephaly NTD cases. Notably, the expression of HOXA10 genes was negatively correlated with CUL4B levels in human anencephaly NTD cases.ConclusionsOur results indicate that abnormal HOX gene expression induced by aberrant CUL4B-mediated H2AK119ub1 levels may be a risk factor for NTDs, and highlight the need for further analysis of genome-wide epigenetic modifications in NTDs.
Highlights
Neural tube defects (NTDs) are common birth defects involving the central nervous system
We investigated whether CUL4B is involved in the retinoic acid (RA)-induced reduction of H2AK119ub1 levels at HOX genes in NT2 human embryonic carcinoma cells (NT2/D1) cells
Chromatin immunoprecipitation (ChIP) analysis showed a decrease in the level of H2AK119ub1 at the HOX gene promoter due to CUL4B siRNA both before and after RA treatment
Summary
Neural tube defects (NTDs) are common birth defects involving the central nervous system. Recent studies on the etiology of human NTDs have raised the possibility that epigenetic regulation could be involved in determining susceptibility to them. A study showed that the formation of the neural tube is under precise spatiotemporal control by cooperative actions between environmental factors and intrinsic signal transduction [1]. The development of NTDs is thought to involve the interplay of genes in the fetus and the effects of environmental factors. Paraxial mesoderm surrounding the neural tube expresses the retinaldehyde dehydrogenase-2 (Raldh2) enzyme, which converts retinaldehyde to RA, serving as a ligand for nuclear RA receptors that directly regulate gene expression at the transcriptional level [4].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
