Genes & development最新文献

The nucleolus and Cajal bodies in the eukaryotic nucleus serve as dynamic hubs for an intricate network of protein-protein and protein-RNA interactions that drive the macromolecular assembly of large and small ribonucleoproteins. However, the mechanisms by which these membrane-less organelles organize their components to fulfill these functions remain largely unknown. In this issue of Genes & Development, Meznad and colleagues (doi:10.1101/gad.353180.125) reveal that the nucleolar and Cajal body protein Nopp140 engages its protein partners through interactions mediated by intrinsically disordered regions. Together, they serve to build the web of interactions required for the tripartite organization of the nucleolus.

Nutrient deficiency during pregnancy in many animal species can induce embryonic diapause, a state characterized by systemic changes in biosynthetic processes that minimize reliance on external energy sources while ensuring survival. Remarkably, these changes do not affect the pluripotent state of embryonic stem (ES) cells, allowing normal development once diapause ends. Here we identify a transcriptional mechanism that maintains ES cell pluripotency during diapause. We show that inhibition of mTOR, which induces a diapause-like state in ES cells, rapidly upregulates genes encoding negative regulators of the MAP kinase (NRMAPK) pathway, a key driver of ES cell differentiation. Elevated NRMAPK expression and associated suppression of MAP kinase activity are also hallmarks of ES cells driven into diapause-like states by long-term inhibition of BET proteins, which regulate differentiation- and growth-promoting gene expression. Suppression of NRMAPK in diapause-like ES cells leads to differentiation and termination of the diapause-like state. Mechanistically, diapause-associated NRMAPK activation involves mTOR or BET inhibition-triggered release of the transcriptional repressor Capicua (CIC) from NRMAPK gene promoters. Our data highlight a key role for mTOR- and BET-controlled transcriptional regulation of MAP kinase activity via negative regulators in maintaining the pluripotent state of diapause ES cells and potentially other metabolically dormant stem or stem-like cells.

Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules bridging a protein with an E3 ubiquitin ligase, promoting its ubiquitylation and degradation. However, PROTACs are not without limitations, including suboptimal target degradation and the "hook effect," a phenomenon where high PROTAC concentrations reduce efficacy due to inactive binary complex formation. In this study, we introduce a novel dual-PROTAC strategy utilizing two distinct E3 ligases, such as KEAP1 and VHL, to synergistically degrade KRAS(G12D) and androgen receptor (AR) by promoting ubiquitin chain elongation and also mitigating the hook effect. In conclusion, a dual-E3 ligase approach represents a promising avenue for optimizing PROTAC-based therapeutics.

FoxA transcription factors pattern gut tissue across animal phylogeny. Beyond their early patterning function, little is known about whether they control the terminal differentiation and/or function of the fully mature enteric nervous system, the intrinsic nervous system of the gut. We show here that the expression and function of the sole Caenorhabditis elegans FoxA homolog, PHA-4, reach beyond its previously described pioneer factor roles in patterning the foregut. Through the engineering of neuron-specific cis-regulatory alleles, Cre-mediated cell-specific knockouts, and degron-mediated, temporally controlled PHA-4/FoxA removal in postmitotic neurons, we found that PHA-4/FoxA is required not only to initiate the terminal differentiation program of foregut-associated enteric neurons but also to maintain their functional properties throughout the life of the animal. Moreover, we discovered novel sites of expression of PHA-4/FoxA in extrapharyngeal enteric neurons that innervate the hindgut (AVL and DVB), a GABAergic interneuron that controls foregut function during sleep (RIS), and a peptidergic neuron (PVT) that we implicate here in controlling defecation behavior. We show that while PHA-4/FoxA is not required for the developmental specification of AVL, DVB, RIS, and PVT, it is required to enable these neurons to control enteric functions. Taken together, PHA-4/FoxA is the only transcription factor known to date that is expressed in and required for the proper function of all distinct types of enteric neurons in a nervous system.