Composite macroH2A/NRF-1 Nucleosomes Suppress Noise and Generate Robustness in Gene Expression

Abstract

The histone variant macroH2A (mH2A) has been implicated in transcriptional repression, but the molecular mechanisms that contribute to global mH2A-dependent genome regulation remain elusive. Using chromatin immunoprecipitation sequencing (ChIP-seq) coupled with transcriptional profiling in mH2A knockdown cells, we demonstrate that singular mH2A nucleosomes occupy transcription start sites of subsets of both expressed and repressed genes, with opposing regulatory consequences. Specifically, mH2A nucleosomes mask repressor binding sites in expressed genes but activator binding sites in repressed genes, thus generating distinct chromatin landscapes that limit genetic or extracellular inductive signals. We show that composite nucleosomes containing mH2A and NRF-1 are stably positioned on gene regulatory regions and can buffer transcriptional noise associated with antiviral responses. In contrast, mH2A nucleosomes without NRF-1 bind promoters weakly and mark genes with noisier gene expression patterns. Thus, the strategic position and stabilization of mH2A nucleosomes in human promoters defines robust gene expression patterns.

Mitochondrial Stress Induces Chromatin Reorganization to Promote Longevity and UPR mt

“…In general, the variance among biological replicates was increased in the lin-65 and met-2 mutants relative to wild type, despite careful handling and harvesting of each of the replicate sets together. Among the possible explanations for increased variance in these mutants, we favor a model where loss of lin-65 or met-2 results in increased transcriptional noise, which is consistent with previous reports that the chromatin environment can epigenetically regulate transcriptional noise in diverse systems (Hansen and O'Shea, 2013, Anderson et al, 2014, Lavigne et al, 2015, Dey et al, 2015). While it will be important to formally address this hypothesis in the future, the data presented here clearly emphasize the importance of lin-65 and met-2 in properly orchestrating the chromatin in order to mount an appropriate response to mitochondrial stress.…”

Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases

“…Evidence suggests that the DNA methylation competes with transcriptions factors [245], which may indicate a possible mechanism for neurodegenerative conditions to take place, if NRF1 binding is affected. NRF1 has also been demonstrated to interact with macroH2A histone which stabilizes and positions nucleosomes and reduces transcriptional variability [246]. NRF1 has also been shown to work with chromosomal conformations to facilitate the expression of GRIN2B, which when affected, results in impairments in working memory [247].…”

MacroH2A histone variants maintain nuclear organization and heterochromatin architecture

“…In both melanoma and breast cancer, macroH2A was, for instance, shown to exert its tumor suppressive function through repression of the cell cycle-promoting gene CDK8 (Kapoor et al, 2010;Xu et al, 2015). Lavigne and colleagues provided results suggesting that rather than being a transcriptional regulator macroH2A proteins stabilize expression states, thus providing robustness and reducing noise (Lavigne et al, 2015).…”