Biology subjects

Gassler, J.

Publications and source records attributed to Gassler, J..

3 recordsLinked to original sources

bioRxiv2022

Zygotic genome activation by the totipotency pioneer factor Nr5a2

Life begins with a switch in genetic control from the maternal to the embryonic genome during zygotic genome activation (ZGA) in totipotent embryos. Despite its importance, the essential regulators of ZGA remain largely unknown in mammals. Based on de novo motif searches, we identified the orphan nuclear receptor Nr5a2 as a key activator of major ZGA in mouse embryos. Nr5a2 binds to its motif within a subtype of SINE B1/Alu transposable elements found in cis-regulatory regions of ZGA genes. Chemical inhibition suggests that 72% of ZGA genes are regulated by Nr5a2 and potentially other orphan nuclear family receptors. Consistent with a role in ZGA, Nr5a2 is required for progression beyond the 2-cell stage. Nr5a2 promotes chromatin accessibility during ZGA and binds to entry/exit sites of nucleosomal DNA in vitro. We conclude that Nr5a2 is an essential pioneer factor that distinctly regulates totipotency and pluripotency during mammalian development. One-Sentence SummaryNr5a2 is an essential pioneer transcription factor that activates expression of zygotic genes in mouse embryos.

developmental biology↗

bioRxiv2020

MCM complexes are barriers that restrict cohesin-mediated loop extrusion

Eukaryotic genomes are compacted into loops and topologically associating domains (TADs), which contribute to transcription, recombination and genomic stability. Cohesin extrudes DNA into loops that are thought to lengthen until CTCF boundaries are encountered. Little is known about whether loop extrusion is impeded by DNA-bound macromolecular machines. We demonstrate that the replicative helicase MCM is a barrier that restricts loop extrusion in G1 phase. Single-nucleus Hi-C of one-cell embryos revealed that MCM loading reduces CTCF-anchored loops and decreases TAD boundary insulation, suggesting loop extrusion is impeded before reaching CTCF. Single-molecule imaging shows that MCMs are physical barriers that frequently constrain cohesin translocation in vitro. Simulations are consistent with MCMs as abundant, random barriers. We conclude that distinct loop extrusion barriers contribute to shaping 3D genomes. One Sentence SummaryMCM complexes are obstacles that impede the formation of CTCF-anchored loops.

cell biology↗

bioRxiv2017

A Mechanism of Cohesin-Dependent Loop Extrusion Organizes Zygotic Genome Architecture

Fertilization triggers assembly of higher-order chromatin structure from a naive genome to generate a totipotent embryo. Chromatin loops and domains are detected in mouse zygotes by single-nucleus Hi-C (snHi-C) but not bulk Hi-C. We resolve this discrepancy by investigating whether a mechanism of cohesin-dependent loop extrusion generates zygotic chromatin conformations. Using snHi-C of mouse knockout embryos, we demonstrate that the zygotic genome folds into loops and domains that depend on Scc1-cohesin and are regulated in size by Wapl. Remarkably, we discovered distinct effects on maternal and paternal chromatin loop sizes, likely reflecting loop extrusion dynamics and epigenetic reprogramming. Polymer simulations based on snHi-C are consistent with a model where cohesin locally compacts chromatin and thus restricts inter-chromosomal interactions by active loop extrusion, whose processivity is controlled by Wapl. Our simulations and experimental data provide evidence that cohesin-dependent loop extrusion organizes mammalian genomes over multiple scales from the one-cell embryo onwards.\n\nHighlightsO_LIZygotic genomes are organized into cohesin-dependent chromatin loops and TADs\nC_LIO_LILoop extrusion leads to different loop strengths in maternal and paternal genomes\nC_LIO_LICohesin restricts inter-chromosomal interactions by altering chromosome surface area\nC_LIO_LILoop extrusion organizes chromatin at multiple genomic scales\nC_LI

genomics↗