RT Journal Article
SR Electronic
T1 Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.18.516861
DO 10.1101/2022.11.18.516861
A1 Irene Mota-Gómez
A1 Juan Antonio Rodríguez
A1 Shannon Dupont
A1 Oscar Lao
A1 Johanna Jedamzick
A1 Ralf Kuhn
A1 Scott Lacadie
A1 Sara Alexandra García-Moreno
A1 Alicia Hurtado
A1 Rafael D. Acemel
A1 Blanche Capel
A1 Marc A. Marti-Renom
A1 Darío G. Lupiáñez
YR 2022
UL http://biorxiv.org/content/early/2022/11/18/2022.11.18.516861.abstract
AB Mammalian sex is determined by opposing networks of ovarian and testicular genes that are well characterized. However, its epigenetic regulation is still largely unknown, thus limiting our understanding of a fundamental process for species propagation. Here we explore the 3D chromatin landscape of sex determination in vivo, by profiling FACS-sorted embryonic mouse gonadal populations, prior and after sex determination, in both sexes. We integrate Hi-C with ChIP-seq experiments using METALoci, a novel genome spatial auto-correlation analysis that identifies 3D enhancer hubs across the genome. We uncover a prominent rewiring of chromatin interactions during sex determination, affecting the enhancer hubs of hundreds of genes that display temporal- and sex-specific expression. Moreover, the identification of the 3D enhancer hubs allows the reconstruction of regulatory networks, revealing key transcription factors involved in sex determination. By combining predictive approaches and validations in transgenic mice we identify a novel Fgf9 regulatory hub, deletion of which results in male-to-female sex reversal with the upregulation of ovarian-specific markers and the initiation of meiosis. Thus, spatial auto-correlation analysis is an effective strategy to identify regulatory networks associated to biological processes and to further characterize the functional role of the 3D genome.Competing Interest StatementMAM-R receives consulting honoraria from Acuity Spatial Genomics, Inc.