Biology subjects

Nickels, J. F.

Publications and source records attributed to Nickels, J. F..

3 recordsLinked to original sources

bioRxiv2024

HP1 binding creates a local barrier against transcription activation and persists during chromatin decondensation

Mouse pericentric repeats form transcriptionally silent and compacted domains known as chromocenters. These prototypic heterochromatin compartments are marked by heterochromatin protein 1 (HP1). However, its contributions to chromocenter structure and function remain debated. We investigated the role of HP1 by recruiting the activators VP16, p65, and VPR to mouse fibroblast chromocenters and analyzed its silencing activity with a transcription reporter. Upon chromocenter decondensation and transcription activation, interactions of HP1 with chromatin and H3K9 trimethylation remained stable, suggesting stoichiometric binding rather than higher-order assembly. HP1-mediated repression required promoter-proximal binding and effectively suppressed VP16-triggered activation but not the stronger activation by VPR. These observations are explained by a 1D lattice binding model, which conceptualizes chromocenters as arrays of repeat units that can independently switch between silenced and activated states. Our findings provide a quantitative framework that explains how chromocenter organization responds to transcriptional activation while maintaining local heterochromatin features. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/627308v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@83816corg.highwire.dtl.DTLVardef@1a603c6org.highwire.dtl.DTLVardef@41d8b4org.highwire.dtl.DTLVardef@fa4d0d_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIHP1 represses transcription at mouse chromocenters and an ectopic reporter when competing with transcriptional activators VP16, p65 and VPR C_LIO_LIHP1 repression requires promoter-proximal binding and effectively counteracts the weak activator VP16 C_LIO_LIThe strong activator VPR overcomes HP1-mediated repression while HP1 remains bound to chromatin C_LIO_LIHP1 binding and H3K9me3 persist during chromocenter decondensation and transcriptional activation C_LIO_LIA 1D lattice binding model explains how independent repeat units transition between silenced and activated states without requiring phase separation C_LI

cell biology↗

bioRxiv2023

The H3.3 K36M oncohistone disrupts the establishment of epigenetic memory through loss of DNA methylation

Histone H3.3 is frequently mutated in cancers, with the lysine 36 to methionine mutation (K36M) being a hallmark of chondroblastomas. While it is known that H3.3K36M changes the cellular epigenetic landscape, it remains unclear how it affects the dynamics of gene expression. Here, we use a synthetic reporter to measure the effect of H3.3K36M on silencing and epigenetic memory after recruitment of KRAB: a member of the largest class of human repressors, commonly used in synthetic biology, and associated with H3K9me3. We find that H3.3K36M, which decreases H3K36 methylation, leads to a decrease in epigenetic memory and promoter methylation weeks after KRAB release. We propose a new model for establishment and maintenance of epigenetic memory, where H3K36 methylation is necessary to convert H3K9me3 domains into DNA methylation for stable epigenetic memory. Our quantitative model can inform oncogenic mechanisms and guide development of epigenetic editing tools.

cell biology↗

bioRxiv2022

Theoretical analysis of confinement mechanisms for epigenetic modifications of nucleosomes

Nucleosomes and their modifications often facilitate gene regulation in eukaryotes. Certain genomic regions may obtain alternate epigenetic states through enzymatic reactions forming positive feedback between nucleosome states. How a system of nucleosome states maintains confinement is an open question. Here we explore a family of stochastic dynamic models with combinations of readwrite enzymes. We find that a larger number of intermediate nucleosome states increases both the robustness of linear spreading in models with only local recruitment processes and the degree of bi-stability under conditions with at least one non-local recruitment. Further, supplementing the positive feedback with one negative feedback acting over long distances along the genome enables effective confinement of epigenetic, bistable regions. Our study emphasizes the importance of determining whether each particular read-write enzyme acts only locally or between distant nucleosomes.

genomics↗