| RRC ID |
90092
|
| Author |
Dogiparthi VR, Chee L, Roy P, Zhou Y, Rowley MJ, Hewitt KJ.
|
| Title |
Predictive modeling of signal-responsive cis-elements in human red blood cell precursors.
|
| Journal |
Nucleic Acids Res
|
| Abstract |
Signal-responsive transcriptional programs are turned on/off by cis-regulatory elements (cis-elements) acting in coordination with gene promoters. While large genomics datasets have annotated common cis-element features, interpreting and predicting specific environmental responses at the chromatin level are critical ongoing challenges. We combined signal-induced chromatin accessibility changes with transcriptomics and a comprehensive catalogue of chromatin occupancy features for predicting functional signaling responses. Using the Kit receptor tyrosine kinase pathway-a central pro-survival, pro-proliferation, and pro-differentiation pathway in hematopoiesis, erythropoiesis, and other tissues-we mapped the sequence and chromatin features at thousands of Kit signal-responsive cis-elements in the human genome. A subset of Kit-induced changes to chromatin occupancy required upregulation of early growth response-1 (EGR1), uncovering distinct EGR1-sensitive and EGR1-insensitive branches of Kit signaling. Predictions of chromatin features associated with signal responses were tested using CRISPR-mediated cis-element disruption, which impaired target gene activation even at very long ranges. These findings define subsets of Kit signaling-dependent cis-regulatory logic which can be applied to interpret how growth factor pathways and cell-type specific transcription factors communicate on chromatin to direct cell behaviors in normal and disease contexts.
|
| Volume |
54(10)
|
| Published |
2026-5-20
|
| DOI |
10.1093/nar/gkag505
|
| PII |
8688742
|
| PMID |
42165135
|
| PMC |
PMC13191290
|
| MeSH |
Chromatin / genetics
Chromatin / metabolism
Early Growth Response Protein 1 / genetics
Early Growth Response Protein 1 / metabolism
Erythropoiesis* / genetics
Gene Expression Regulation
Genome, Human
Humans
Promoter Regions, Genetic
Proto-Oncogene Proteins c-kit* / genetics
Proto-Oncogene Proteins c-kit* / metabolism
Signal Transduction / genetics
|
| Resource |
| Human and Animal Cells |
HUDEP-2(RCB4557) |
