Retinoid X receptor promotes hematopoietic stem cell fitness and quiescence by repressing MYC pathway activation [RXR_ATACSeq]

Hematopoietic stem cells (HSCs) maintain homeostasis and fitness by balancing self-renewal and differentiation. Alterations to the symmetry of HSC divisions reduce quiescence and induce myeloid/megakaryocyte-biased hematopoiesis. Here, we show that HSC self-renewal, fitness, and function are preserved by the master transcription factor retinoid X receptor (RXR). We demonstrate that dual lack of hematopoietic RXRa and RXRß induces HSC asymmetric cell division resulting in HSC exhaustion and age-associated myeloproliferative disease. Characterization of transcriptomic and epigenetic changes in RXR-deficient HSCs demonstrated chromatin opening, acquisition of a premature aging-like HSC signature, MYC pathway upregulation, and RNA intron retention. Myc haploinsufficiency completely prevents the loss of RXR-deficient HSC activity. Our study unveils the critical relevance of RXR for HSC homeostasis and fitness. Overall design: The chromatin accessibility profiles of LT-HSCs and MPPs were generated using sorted bone marrow cells from WT and RXR-KO mice. Transposition was performed using Tn5 enzyme. (Illumina), applying size selection. Sequencing was performed in duplicate using 2×50 HiSeq 3000 (Illumina) and with an average of 25 million paired-end reads per sample.Here, we performed a low input bulk RNAseq experiment. LT-HSCs and MPPs were sorted and total RNA was extracted using Arcturus PicoPure kit. Then, RNA samples (5ng) were used for library preparation. Libraries followed next generation paired end sequencing.