bims-caglex 2026-04-05 papers

Stem Cell Reports. 2026 Apr 02. pii: S2213-6711(26)00081-0. [Epub ahead of print] 102870

Dose-resolved control of somatic reprogramming by Rora.

Nuclear receptors (NRs) are ligand-regulated transcription factors whose domains and dosage modulate gene networks. We systematically profiled 49 murine NRs in OKS (OCT4/KLF4/SOX2) reprogramming of mouse fibroblasts and identified the ROR subfamily as enhancers. Focusing on Rora, we uncovered a dose-dependent, biphasic effect on reprogramming: moderate Rora increases OCT4-GFP+ colony formation, whereas higher expression reduces colonies. Domain dissection separated these arms-DNA-binding domain (DBD)/ligand-binding domain (LBD) was required for the pro-reprogramming effect, while the N-terminal domain (NTD) was required for high-dose inhibition (ΔNTD eliminated the inhibitory limb). Functionally, the reprogramming barrier interferon (IFN)-γ was attenuated at transcript and protein levels; IFN-γ add-back dampened the enhancement, supporting immune-axis modulation. Conversely, WNT pathway output was reduced in the inhibitory arm, and CHIR99021 partially rescued the high-dose colony defect. Thus, RORA acts as a dose-programmed, domain-modular regulator that coordinates chromatin and signaling to gate cell-fate conversion, establishing nuclear-receptor dosage control as a lever to improve reprogramming efficiency.

Keywords: Rora; dose-dependent regulation; nuclear receptors; somatic cell reprogramming

DOI: https://doi.org/10.1016/j.stemcr.2026.102870

Proc Natl Acad Sci U S A. 2026 Apr 07. 123(14): e2517488123

Regulation of STK38 by autophagy governs YAP1 activity during paligenosis.

Yongji Zeng, Yang-Zhe Huang, Qing Kay Li, Raymond Ho, Steven J Bark, Spencer G Willet, Richard J DiPaolo, Jason C Mills.

Paligenosis is a conserved cellular plasticity program that allows mature cells to reenter the cell cycle in response to tissue injury. Paligenosis progresses via three stages: autodegradation (with dramatic increase in autophagy and lysosomes), induction of metaplastic or fetal-like genes, and cell cycle entry. Hippo signaling, particularly the downstream effector YAP1, regulates cellular plasticity, but its role in paligenosis has not been studied. Here, we examine YAP1 dynamics during paligenosis in digestive-enzyme-secreting chief cells from the mouse stomach. We identified Serine/Threonine Kinase 38 (STK38) as a noncanonical YAP1 kinase that phosphorylates and deactivates YAP1 in uninjured chief cells. During paligenosis, STK38 was degraded by autophagy in stage 1, dephosphorylating and activating YAP1. YAP1 activation was necessary and sufficient for paligenosis-driven conversion of chief cells into metaplastic, proliferating progenitors. Additionally, we show that STK38, like canonical Hippo kinases, interacts with Neurofibromatosis Type 2 (Merlin), a scaffold that recruits Hippo kinases to phosphorylate YAP1. We also observed the same pattern of YAP1 induction via autophagic destruction of STK38 in other tissues and cell types, suggesting injury-induced activation of autophagy in differentiated cells during tissue damage may be a more general feature by which Hippo effectors induce plasticity for regeneration.

Keywords: Hippo pathway; redifferentiation; reprogramming

DOI: https://doi.org/10.1073/pnas.2517488123

Aging Dis. 2026 Mar 20.

Fundamental Cell-Intrinsic Mechanism Underlying Age-Dependent Accumulation of Senescent Cells.

Pavel I Deryabin, Aleksandra V Borodkina.

The accumulation of senescent cells during aging contributes to the progression of various age-related pathologies. Ineffective immune clearance, increased half-life of senescent cells, and bystander senescence are considered the primary drivers of this age-associated accumulation. Most of these causes stem from the aging of the immune system, which results in a prolonged persistence of damaged/nonfunctional cells within tissues and allows the internal senescence program to progress to a more severe phenotype. Here, we propose the existence of an additional immune-independent mechanism underlying the accumulation of senescent cells during aging. By reanalyzing existing experimental evidence, we show that cells of diverse identities and tissue origins become increasingly susceptible to senescence with age. The latter implies that epigenetic and molecular changes that cells acquire during aging create a permissive background for the activation of the senescence program. In light of our findings, senotherapeutic interventions alone may be insufficient to substantially alter the trajectory of organismal aging. Effective strategies may need to target upstream drivers of cellular dysfunction, including age-associated epigenetic alterations. Epigenetic rejuvenation could, in principle, enhance cellular stress resilience and thereby reduce the rate at which senescent cells emerge and accumulate.

DOI: https://doi.org/10.14336/AD.2026.0137

Nat Aging. 2026 Mar 31.

Multiomic single-cell perturbation screens reveal critical lncRNA regulators of senescence.

Shouxuan Zhu, Sunyang Ying, Donghong Cai, Ya Ren, Luoxi Wang, Zhi Qi, Vera Gorbunova, Jing-Dong J Han.

Long noncoding RNAs (lncRNAs) regulate transcriptional and epigenetic programs during aging and senescence. However, no comprehensive studies have systematically integrated multilayered analyses to reveal their diverse regulatory roles. Moreover, lncRNAs with therapeutic potential in age-related diseases remain unexplored. Here we systematically perturbed 32 high-abundance aging- and senescence-associated lncRNAs (PtbAlncs) using a Perturb-seq-based CRISPR-dCas9-KRAB knockdown system coupled with single-nucleus multiomics profiling, enabling simultaneous transcriptomic and chromatin accessibility analysis. This analysis uncovered essential roles for previously uncharacterized lncRNAs in senescence regulation, validated computationally and experimentally. These lncRNAs modulate distinct single-cell RNA-sequencing modules through diverse yet overlapping epigenetic motifs in single-cell ATAC-sequencing modules. Among them, HOTAIRM1, a DNA repair-associated PtbAlnc, stabilizes DNA repair by cooperating with BANF1 and p53 at double-strand break loci within condensates. Its deficiency impairs DNA repair and triggers p53-mediated senescence. In aged mouse lungs, adeno-associated virus-mediated HOTAIRM1 overexpression reduced fibrosis, alleviated tissue damage, and promoted cellular proliferation, underscoring its therapeutic potential.

DOI: https://doi.org/10.1038/s43587-026-01100-7