Karatepe, K. | bioRxiv Science

bioRxiv2024

Linker histone regulates the myeloid versus lymphoid bifurcation of multipotent hematopoietic stem and progenitors

Myeloid-biased differentiation of multipotent hematopoietic stem and progenitor cells (HSPCs) occurs with aging or exhaustion. The molecular mechanism(s) responsible for this fate bias remain unclear. Here we report that linker histone regulates HSPC fate choice at the lymphoid versus myeloid bifurcation. HSPCs expressing H1.0 from a doxycycline (dox) inducible transgene favor the lymphoid fate, display strengthened nucleosome organization and reduced chromatin accessibility at genomic regions hosting key myeloid fate drivers. The transcription factor Hlf is located in one of such regions, where chromatin accessibility and gene expression is reduced in H1.0high HSPCs. Furthermore, H1.0 protein in HSPCs decreases in an aspartyl protease dependent manner, a process enhanced in response to interferon alpha (IFN) signaling. Aspartyl protease inhibitors preserve endogenous H1.0 levels and promote the lymphoid fate of wild type HSPCs. Thus, our work uncovers a point of intervention to mitigate myeloid skewed hematopoiesis.

developmental biology↗

bioRxiv2023

Finetuning ERK activity enables most somatic cells to reprogram into pluripotency

Cell morphology is faithfully coupled to its identity but the coupling mechanism remains elusive. Using somatic cell reprogramming into pluripotency as a model system, we show that activity of the extracellular signal-regulated kinase (ERK) is tuned by cellular morphomechanic state to direct cell fate. Pluripotent cells and somatic cells reprogramming into pluripotency allocate large amounts of actin into their nucleus, which morphs cells to become taller than 10 m, a minimal height required for the pluripotent identity. Accumulated nuclear actin binds to TFII-I{Delta}, an atypical transcription factor that translocates into the nucleus upon signaling. TFII-I{Delta} also binds to and activates ERK. The binding of TFII-I{Delta} by nuclear actin reduces ERK activity, in coordination with changes in cell/colony height. The tight coupling between cell height and nuclear actin accumulation necessitates the degree of ERK tuning to be mild. Mild ERK inhibition by chemicals recapitulates the tuning by actin-TFII-I{Delta} and turns most cells in reprogramming cultures into pluripotency. Thus, we uncover a novel mechanism for how cell morphology couples to its identity via the actin-TFII-I{Delta}-ERK axis, identifying points of intervention in cell fate manipulation.

cell biology↗