Biology subjects

Chomiak, A. A.

Publications and source records attributed to Chomiak, A. A..

3 recordsLinked to original sources

bioRxiv2021

Nde1 is Required for Heterochromatin Compaction and Stability in Neocortical Neurons

The NDE1 gene encodes a scaffold protein essential for brain development. While biallelic NDE1 loss of function (LOF) causes microcephaly with profound mental retardation, NDE1 missense mutations and copy number variations are associated with multiple neuropsychiatric disorders. However, the etiology of the diverse phenotypes resulting from NDE1 aberrations remains elusive. Here we show Nde1 controls neurogenesis through facilitating heterochromatin compaction via histone H4K20 trimethylation. This mechanism patterns diverse chromatin landscapes and stabilizes constitutive heterochromatin of neocortical neurons. We show NDE1 undergoes dynamic liquid-liquid phase separation, partitioning to the nucleus and interacting with pericentromeric and centromeric satellite repeats. Nde1 LOF results in nuclear architecture aberrations and DNA double strand breaks, as well as instability and derepression of pericentromeric satellite repeats in neocortical neurons. These findings uncover a pivotal role of NDE1/Nde1 in establishing and maintaining neuronal heterochromatin. They suggest that heterochromatin impairments underlie a wide range of brain dysfunction.

genetics↗

bioRxiv2020

Histone H2A ubiquitination resulting from Brap loss of function connects multiple aging hallmarks and accelerates neurodegeneration

Aging is an intricate process that is characterized by multiple hallmarks including stem cell exhaustion, genome instability, epigenome alteration, impaired proteostasis, and cellular senescence. While each of these traits is detrimental at the cellular level, it remains unclear how they are interconnected to cause systemic organ deterioration. Here we show that abrogating Brap, a BRCA1 associated protein important for neurogenesis, results in cellular senescence with persistent DNA double-strand breaks and elevation of histone H2A mono- and poly-ubiquitination (H2Aub). The high H2Aub initiates histone proteolysis, leading to both epigenetic alteration and proteasome overflow. These defects induce neuroinflammation, impair proteostasis, accelerate neurodegeneration, and substantially shorten lifespan in mice carrying Brap deletions in the brain. We further show H2Aub is also increased in human brain tissues of Alzheimers disease. These data together suggest that chromatin aberrations mediated by H2Aub act as a nexus of multiple aging hallmarks and promote tissue-wide degeneration.

neuroscience↗

bioRxiv2019

siQ-ChIP:A reverse-engineered quantitative framework for ChIP-sequencing

Chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) is a key technique for mapping the distribution and relative abundance of histone posttranslational modifications (PTMs) and chromatin-associated factors across genomes. There is a perceived challenge regarding the ability to quantitatively plot ChIP-seq data, and as such, approaches making use of exogenous additives, or \"spike-ins\" have recently been developed. Relying on the fact that the IP step of ChIP-seq is a competitive binding reaction, we present a quantitative framework for ChIP-seq analysis that circumvents the need to modify standard sample preparation pipelines with spike-in reagents. We also introduce a visualization technique that, when paired with our formal developments, produces a much more rich characterization of sequencing data.

genomics↗