Regulation of Sox8 through lncRNA Mrhl-Mediated Chromatin Looping in Mouse Spermatogonia

ABSTRACT

Sox8 is a developmentally important transcription factor that plays an important role in sex maintenance and fertility of adult mice. In the B-type spermatogonial cells, Sox8 is regulated by the long noncoding RNAs (lncRNA) Mrhl in a p68-dependant manner under the control of the Wnt signaling pathway. The downregulation of Mrhl leads to the meiotic commitment of the spermatogonial cells in a Sox8-dependant manner. While the molecular players involved in the regulation of transcription at the Sox8 promoter have been worked out, our current study points to the involvement of the architectural proteins CTCF and cohesin in mediating a chromatin loop that brings the Sox8 promoter in contact with a silencer element present within the gene body in the presence of lncRNA Mrhl concomitant with transcriptional repression. Further, lncRNA Mrhl interacts with the Sox8 locus through the formation of a DNA:DNA:RNA triplex, which is necessary for the recruitment of PRC2 to the locus. The downregulation of lncRNA Mrhl results in the promoter-silencer loop giving way to a promoter-enhancer loop. This active transcription-associated chromatin loop is mediated by YY1 and brings the promoter in contact with the enhancer present downstream of the gene.

KEYWORDS:

• 3D chromatin organization
• epigenetics
• gene regulation
• lncRNA

Declaration of Interests

The authors declare no conflict of interest.

ACKNOWLEDGMENTS

This work was supported by the Department of Biotechnology, India (BT/01/COE/07/09 and DBT/INF/22/SP27679/2018).

M.R.S.R. acknowledges Department of Science and Technology for J. C. Bose and S.E.R.B. Distinguished fellowships and The Year of Science Chair professorship.

We declare no competing interests.