Common variants in signaling transcription-factor-binding sites drive phenotypic variability in red blood cell traits

Abstract

substantial fraction of worldwide mortality is attributed to erythrocyte-related disorders 1-7. Variation in RBC traits is linked to mortality rates not related to primary hematologic disease 1,3,6. Genome-wide association studies (GWAS) have identified numerous variable genomic regions associated with human traits and diseases, including RBC traits 8-21. RBC-trait-associated single-nucleotide polymorphisms (SNPs) rarely affect DNA binding of MTFs, such as GATA2 and GATA1, even though they are often in close proximity to MTF target sequences 15,22,23. Additional mechanisms by which RBC SNPs result in the phenotypic variability of human genetic traits remain to be discovered. Environmental factors contribute to the phenotypic manifestation of complex human genetic traits 1,3,6. Under stress conditions, growth factors and small molecules activate signaling pathways 24-26 that converge on signal-induced effector transcription factors (STFs) to control gene expression. By coordinating with MTFs, the same STFs may be active in multiple cell types but exert tissue-specific functions 27,28. Hence, alterations in STF target sequences may lead to aberrant responses to various signals. Here, we observed that human erythroid-trait-associated non-coding SNPs are enriched in a small subset of enhancers co-bound by MTFs and STFs, which we named transcriptional sig

External signals regulate continuous transcriptional states in hematopoietic stem cells

“…Interestingly, we observed heterogeneity of HSC responses to external stimuli which may be determined by the baseline transcriptional and epigenetic state supported by our single-cell chromatin studies. Preliminary findings suggested an HSC specific co-occurrence of signaling and lineage-specific TF motif activities that is consistent with previous observations in human hematopoietic progenitors ( Trompouki et al, 2011 ; Choudhuri et al, 2020 ). Overall, our data indicates that the single-cell landscape of in vivo-derived, functional HSCs is likely made up of a unique chromatin architecture with fluent transcriptional states, some of which can be rapidly influenced by external signals.…”

Niche signals regulate continuous transcriptional states in hematopoietic stem cells

“…Our single cell chromatin studies indicate cell intrinsic HSC heterogeneity that predisposes subpopulations for certain transcriptional responses. We detected an HSC specific co-occurrence of signaling and lineage-specific transcription factor motif activities that is consistent with our previous observation in human hematopoietic progenitors (Trompouki et al, 2011, Choudhuri et al, 2020)). Absence of similar chromatin features in LSK progenitors may implicate a link to some of the unique functional capacities of HSCs, such as self-renewal.…”

Single-cell ATAC-seq reveals GATA2-dependent priming defect in myeloid and a maturation bottleneck in lymphoid lineages

“…GATA2 ChIP-seq in CD34 1 cells Experimental details are described by Choudhuri and colleagues. 29 Briefly, human CD34 1 cells were purchased from the Fred Hutchinson Cancer Research Center and maintained as previously described. 30 After 6 days of expansion, the cells were stimulated for 2 hours with rhBMP4 (R&D) at a final concentration of 25 ng/mL and harvested for performing chromatin immunoprecipitation with sequencing (ChIP-seq), with GATA2 antibody (Santa Cruz).…”