bims-ectoca 2023-12-31 papers

Issue of 2023‒12‒31
three papers selected by
Ankita Daiya, BITS Pilani

Dev Cell. 2023 Dec 18. pii: S1534-5807(23)00650-0. [Epub ahead of print]

YAP and TAZ couple osteoblast precursor mobilization to angiogenesis and mechanoregulation in murine bone development.

Joseph M Collins, Annemarie Lang, Cristian Parisi, Yasaman Moharrer, Madhura P Nijsure, Jong Hyun Thomas Kim, Saima Ahmed, Gregory L Szeto, Ling Qin, Riccardo Gottardi, Nathaniel A Dyment, Niamh C Nowlan, Joel D Boerckel.

Fetal bone development occurs through the conversion of avascular cartilage to vascularized bone at the growth plate. This requires coordinated mobilization of osteoblast precursors with blood vessels. In adult bone, vessel-adjacent osteoblast precursors are maintained by mechanical stimuli; however, the mechanisms by which these cells mobilize and respond to mechanical cues during embryonic development are unknown. Here, we show that the mechanoresponsive transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) spatially couple osteoblast precursor mobilization to angiogenesis, regulate vascular morphogenesis to control cartilage remodeling, and mediate mechanoregulation of embryonic murine osteogenesis. Mechanistically, YAP and TAZ regulate a subset of osteoblast-lineage cells, identified by single-cell RNA sequencing as vessel-associated osteoblast precursors, which regulate transcriptional programs that direct blood vessel invasion through collagen-integrin interactions and Cxcl12. Functionally, in 3D human cell co-culture, CXCL12 treatment rescues angiogenesis impaired by stromal cell YAP/TAZ depletion. Together, these data establish functions of the vessel-associated osteoblast precursors in bone development.

Keywords: TAZ; YAP; angiogenesis; bone; development; growth plate; mechanobiology

DOI: https://doi.org/10.1016/j.devcel.2023.11.029

Gene. 2023 Dec 25. pii: S0378-1119(23)00951-4. [Epub ahead of print] 148110

Solute carrier family 35 member A2 regulates mitophagy through the PI3K/AKT/mTOR axis, promoting the proliferation, migration, and invasion of osteosarcoma cells.

Xiaohui Luo, Jiongfeng Zhang, Chong Guo, Ning Jiang, Feifei Zhang, Quahui Jiao, Kai Xu, Jun Yang, Gaoyang Qu, Xiao-Bin Lv, Zhiping Zhang.

The treatment of osteosarcoma patients exhibits individual variability, underscoring the critical importance of targeted therapy. Although (Solute carrier family 35 member A2) SLC35A2's role in the progression of various cancers has been extensively investigated, its specific implications in osteosarcoma remain unexplored. Leveraging data from the (The Cancer Genome Atlas) TCGA and (Genotype-Tissue Expression) GTEx databases, we have discerned that SLC35A2 is notably upregulated in osteosarcoma and correlates with the prognosis of osteosarcoma patients. Consequently, it becomes imperative to delve into the role of SLC35A2 in the context of osteosarcoma. Our research substantiates that SLC35A2 exerts a notable influence on mitochondrial autophagy in osteosarcoma, thereby exerting cascading effects on the proliferation, migration, invasion, and apoptosis of osteosarcoma cells. Mechanistically, SLC35A2 orchestrates mitochondrial autophagy via the PI3K/AKT/mTOR signaling pathway. Moreover, we have conducted rigorous animal experiments to further corroborate the repercussions of SLC35A2 on osteosarcoma growth. In summation, our study elucidates that SLC35A2's modulation of mitochondrial autophagy through the PI3K/AKT/mTOR signaling pathway constitutes a pivotal factor in the malignant progression of osteosarcoma, unveiling promising therapeutic targets for patients grappling with this condition.

Keywords: Mitophagy; Osteosarcoma; PI3K/SKT/mTOR; SLC35A2

DOI: https://doi.org/10.1016/j.gene.2023.148110

Mol Cell. 2023 Dec 20. pii: S1097-2765(23)01012-2. [Epub ahead of print]

Collisions of RNA polymerases behind the replication fork promote alternative RNA splicing in newly replicated chromatin.

Federica Bruno, Cristóbal Coronel-Guisado, Cristina González-Aguilera.

DNA replication produces a global disorganization of chromatin structure that takes hours to be restored. However, how these chromatin rearrangements affect the regulation of gene expression and the maintenance of cell identity is not clear. Here, we use ChOR-seq and ChrRNA-seq experiments to analyze RNA polymerase II (RNAPII) activity and nascent RNA synthesis during the first hours after chromatin replication in human cells. We observe that transcription elongation is rapidly reactivated in nascent chromatin but that RNAPII abundance and distribution are altered, producing heterogeneous changes in RNA synthesis. Moreover, this first wave of transcription results in RNAPII blockages behind the replication fork, leading to changes in alternative splicing. Altogether, our results deepen our understanding of how transcriptional programs are regulated during cell division and uncover molecular mechanisms that explain why chromatin replication is an important source of gene expression variability.

Keywords: ChOR-seq; RNAPII; cell division; cell identity; chromatin; gene expression; replication; splicing; transcription; transcription-replication conflicts

DOI: https://doi.org/10.1016/j.molcel.2023.11.036