Biology subjects

Nickels, J. F.

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

2 recordsLinked to original sources

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↗