Mrhl Long Noncoding RNA Mediates Meiotic Commitment of Mouse Spermatogonial Cells by Regulating Sox8 Expression

ABSTRACT

Long noncoding RNAs (lncRNAs) are important regulators of various biological processes, including spermatogenesis. Our previous studies have revealed the regulatory loop of mrhl RNA and Wnt signaling, where mrhl RNA negatively regulates Wnt signaling and gets downregulated upon Wnt signaling activation. This downregulation of mrhl RNA is important for the meiotic progression of spermatogonial cells. In our present study, we identified the transcription factor Sox8 as the regulatory link between mrhl RNA expression, Wnt signaling activation, and meiotic progression. In contrast to reports from other groups, we report the expression of Sox8 in germ cells and describe the molecular mechanism of Sox8 regulation by mrhl RNA during differentiation of spermatogonial cells. Binding of mrhl RNA to the Sox8 promoter is accompanied by the assembly of other regulatory factors involving Myc-Max-Mad transcription factors, corepressor Sin3a, and coactivator Pcaf. In the context of Wnt signaling, Sox8 directly regulates the expression of premeiotic and meiotic markers. Prolonged Wnt signaling activation in spermatogonial cells leads to changes in global chromatin architecture and a decrease in levels of stem cell markers.

KEYWORDS:

• Myc-Mad-Max
• Sin3A
• Sox8
• Wnt signaling
• mrhl RNA

ACKNOWLEDGMENTS

We thank Jomon Joseph of the National Centre for Cell Sciences (NCCS, India) for providing the mouse L cells. We acknowledge A. Prakash of the Animal Facility, B. S. Suma of the Confocal Imaging Facility, and Y. Swaroopa of the FACS Facility at JNCASR. M.R.S.R. thanks the Department of Science and Technology for J. C. Bose and SERB Distinguished Fellowships.

This work was financially supported by Department of Biotechnology, Govt. of India (Grant Number BT/01/COE/07/09).

We declare that we have no conflicts of interest.

S.K. and B.K. performed the experiments. S.K., V.S.A., and M.R.S.R. designed the experiments, analyzed the data, and wrote the manuscript.