Systematic epigenome editing captures the context-dependent instructive function of chromatin modifications.
Nat Genet
; 56(6): 1168-1180, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38724747
ABSTRACT
Chromatin modifications are linked with regulating patterns of gene expression, but their causal role and context-dependent impact on transcription remains unresolved. Here we develop a modular epigenome editing platform that programs nine key chromatin modifications, or combinations thereof, to precise loci in living cells. We couple this with single-cell readouts to systematically quantitate the magnitude and heterogeneity of transcriptional responses elicited by each specific chromatin modification. Among these, we show that installing histone H3 lysine 4 trimethylation (H3K4me3) at promoters can causally instruct transcription by hierarchically remodeling the chromatin landscape. We further dissect how DNA sequence motifs influence the transcriptional impact of chromatin marks, identifying switch-like and attenuative effects within distinct cis contexts. Finally, we examine the interplay of combinatorial modifications, revealing that co-targeted H3K27 trimethylation (H3K27me3) and H2AK119 monoubiquitination (H2AK119ub) maximizes silencing penetrance across single cells. Our precision-perturbation strategy unveils the causal principles of how chromatin modification(s) influence transcription and dissects how quantitative responses are calibrated by contextual interactions.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cromatina
/
Histonas
/
Edição de Genes
/
Epigenoma
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article