The epigenetic eraser LSD1 lies at the apex of a reversible erythroid to myeloid cell fate decision

Abstract

Histone H3 lysine 4 methylation (H3K4Me) is proximally associated with chromatin activation, and therefore removing H3K4 methyl groups is normally coincident with gene repression. H3K4Me demethylase KDM1a/LSD1 is a potential therapeutic target for multiple diseases, including for the treatment of the β-globinopathies (sickle cell disease and β-thalassemia) since it is a component of multiple γ-globin repressor complexes, and its inactivation leads to robust induction of the fetal globin genes. However, the effects of LSD1 inhibition in definitive erythroid cells are not well characterized. Here we examined the consequences of erythroid-specific conditional inactivation of Lsd1 in vivo using a new Gata1creERT2 bacterial artificial chromosome (BAC) transgene. Conditional loss of Lsd1 in adult mice led to a differentiation block in erythroid progenitor cells and the surprising expansion of a GMP-like cell pool, apparently converting hematopoietic differentiation potential from an erythroid to a myeloid fate. The analogous phenotype was also observed in human cells: inactivation of LSD1 in hematopoietic stem and progenitor cells (HSPC) also blocked erythroid differentiation, coincident with robust induction of myeloid transcription factor genes (e.g. Pu.1 and Cebpa). Remarkably, blocking the activity of PU.1 or RUNX1 (a transcriptional activator of Pu.1) at the same time as blocking LSD1 activity reverted the myeloid lineage conversion back to an erythroid phenotype. Taken together, the data show that LSD1 maintains erythropoiesis by reversibly repressing a myeloid cell fate in adult erythroid cell precursors, and that inhibition of the myeloid differentiation pathway can reverse the negative effects of LSD1 inactivation on erythroid differentiation.

Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq

“…Surprisingly, loss of a number of common essential genes (i.e., essential across cell lines in the Cancer Dependency Map) also caused expression of either myeloid (e.g., Integrator subcomplex) or erythroid (e.g., NuRD complex, DNA replication machinery) markers. Next, we investigated the differentiation effect of selectively essential genes, which could be promising targets for differentiation therapy, analogous to ongoing efforts for KDM1A (39,40). We observed that loss of PTPN1, a tyrosine phosphatase selectively essential in K562 cells, drove myeloid differentiation.…”

High-throughput methods for the analysis of transcription factors and chromatin modifications: Low input, single cell and spatial genomic technologies

“…The fundamental roles played by TFs have been highlighted by numerous knock-out studies throughout the past decades showing that disrupting TF function can completely impair tissue formation, cellular differentiation or can induce dramatic changes in cell fate (e.g. [1][2][3][4]). Enforcing TF expression may also reprogram differentiated cells towards stem cell-like state or can induce a switch towards a different lineage identity, further underscoring their critical functions [5,6].…”