Deacetylation of FOXP1 by HDAC7 potentiates self-renewal of mesenchymal stem cells.

BACKGROUND: Mesenchymal stem cells (MSCs) are widely used in a variety of tissue regeneration and clinical trials due to their multiple differentiation potency. However, it remains challenging to maintain their replicative capability during in vitro passaging while preventing their premature cellular senescence. Forkhead Box P1 (FOXP1), a FOX family transcription factor, has been revealed to regulate MSC cell fate commitment and self-renewal capacity in our previous study. METHODS: Mass spectra analysis was performed to identify acetylation sites in FOXP1 protein. Single and double knockout mice of FOXP1 and HDAC7 were generated and analyzed with bone marrow MSCs properties. Gene engineering in human embryonic stem cell (hESC)-derived MSCs was obtained to evaluate the impact of FOXP1 key modification on MSC self-renewal potency. RESULTS: FOXP1 is deacetylated and potentiated by histone deacetylase 7 (HDAC7) in MSCs. FOXP1 and HDAC7 cooperatively sustain bone marrow MSC self-renewal potency while attenuating their cellular senescence. A mutation within human FOXP1 at acetylation site (T176G) homologous to murine FOXP1 T172G profoundly augmented MSC expansion capacity during early passages. CONCLUSION: These findings reveal a heretofore unanticipated mechanism by which deacetylation of FOXP1 potentiates self-renewal of MSC and protects them from cellular senescence. Acetylation of FOXP1 residue T172 as a critical modification underlying MSC proliferative capacity. We suggest that in vivo gene editing of FOXP1 may provide a novel avenue for manipulating MSC capability during large-scale expansion in clinical trials.

FOXP4 differentially controls cold-induced beige adipocyte differentiation and thermogenesis.

Beige adipocytes have a discrete developmental origin and possess notable plasticity in their thermogenic capacity in response to various environmental cues, but the transcriptional machinery controlling beige adipocyte development and thermogenesis remains largely unknown. By analyzing beige adipocyte-specific knockout mice, we identified a transcription factor, forkhead box P4 (FOXP4), that differentially governs beige adipocyte differentiation and activation. Depletion of Foxp4 in progenitor cells impaired beige cell early differentiation. However, we observed that ablation of Foxp4 in differentiated adipocytes profoundly potentiated their thermogenesis capacity upon cold exposure. Of note, the outcome of Foxp4 deficiency on UCP1-mediated thermogenesis was confined to beige adipocytes, rather than to brown adipocytes. Taken together, we suggest that FOXP4 primes beige adipocyte early differentiation, but attenuates their activation by potent transcriptional repression of the thermogenic program.

Forkhead box P1 (Foxp1) in osteoblasts regulates bone mass accrual and adipose tissue energy metabolism.

Adiponectin (AdipoQ), a hormone abundantly secreted by adipose tissues, has multiple beneficial functions, including insulin sensitization as well as lipid and glucose metabolism. It has been reported that bone controls energy metabolism through an endocrine-based mechanism. In this study, we observed that bone also acts as an important endocrine source for AdipoQ, and its capacity in osteoblasts is controlled by the forkhead box P1 (FOXP1) transcriptional factor. Deletion of the Foxp1 gene in osteoblasts led to augmentation of AdipoQ levels accompanied by fueled energy expenditure in adipose tissues. In contrast, overexpression of Foxp1 in bones impaired AdipoQ secretion and restrained energy consumption. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis revealed that AdipoQ expression, which increases as a function of bone age, is directly controlled by FOXP1. Our results indicate that bones, especially aged bones, provide an important source of a set of endocrine factors, including AdipoQ, that control body metabolism. © 2021 American Society for Bone and Mineral Research (ASBMR).