Critical Modulation of Hematopoietic Lineage Fate by Hepatic Leukemia Factor

Abstract

SummaryA gradual restriction in lineage potential of multipotent stem/progenitor cells is a hallmark of adult hematopoiesis, but the underlying molecular events governing these processes remain incompletely understood. Here, we identified robust expression of the leukemia-associated transcription factor hepatic leukemia factor (Hlf) in normal multipotent hematopoietic progenitors, which was rapidly downregulated upon differentiation. Interference with its normal downregulation revealed Hlf as a strong negative regulator of lymphoid development, while remaining compatible with myeloid fates. Reciprocally, we observed rapid lymphoid commitment upon reduced Hlf activity. The arising phenotypes resulted from Hlf binding to active enhancers of myeloid-competent cells, transcriptional induction of myeloid, and ablation of lymphoid gene programs, with Hlf induction of nuclear factor I C (Nfic) as a functionally relevant target gene. Thereby, our studies establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage-restricted progeny, with implications for both normal and malignant hematopoiesis.

Bayesian integrative analysis of epigenomic and transcriptomic data identifies Alzheimer's disease candidate genes and networks

“…The first subnetwork ( Fig 4A) was enriched with genes involved in myeloid cell differentiation (S4 Table) and reflected the immune component of AD [67]. The network included myeloid transcription factors such as NFIC [68], and cytokines such as CSF1 and the corresponding receptor CSF1R, which have recently been studied in the context of microglia activation [69][70][71]. Cellular functions of the upregulated genes RHOQ and TRIP10 include endocytosis and regulation of cell shape and motility [72,73].…”

Hepatic Leukemia Factor Maintains Quiescence of Hematopoietic Stem Cells and Protects the Stem Cell Pool during Regeneration

“…To determine whether HLF directly binds to regulatory elements of genes regulating HSC activity, we obtained chromatin immunoprecipitation sequencing (ChIP-seq) data from mouse LSK cells overexpressing Hlf (Wahlestedt et al, 2017). The dataset identified 693 genes bound by HLF, with a binding motif similar to the known HLF-binding site described in Wahlestedt et al (2017).…”

“…By overlapping ChIP targets with the significantly regulated genes, we identified a set of transcription factors that were all downregulated in Hlf À/À HSCs ( Figure 3F). Among these transcription factors, we found Nfic (identified as a direct target of HLF in Wahlestedt et al, 2017) and Irf2, which is an important regulator of HSC quiescence (Sato et al, 2009) ( Figure 3F). When intersecting the HLF-binding data with ChIP-seq data of active histone marks in HSC and assay for transposase-accessible chromatin (ATAC) sequencing data in LSK cells (Wahlestedt et al, 2017), we could confirm that HLF directly binds to the promoter region (surrounded by active histone marks) as well as to possible enhancer regions of Irf2 ( Figure 3G).…”

“…The enrichment plots were obtained using curated gene sets in GSEA MSigDB and were obtained by adding the costume made gene sets (generated from GEO: GSE9189 by comparing LT-HSC and ST-HSC p < 0.01 and fold-change threshold of 2 as a filter) to the curated gene sets in GSEA MSigDB. ChIP-seq was performed as described previously (Wahlestedt et al, 2017). Briefly, peak regions were called using MACS2 (Zhang et al, 2008) and density plots generated in bigwig format.…”

“…The accession numbers for the RNA-seq and ChIP-seq data reported in this study are GEO: GSE100385 and GEO: GSE69817 (Wahlestedt et al, 2017), respectively.…”