bims-raghud 2025-12-14 papers

Issue of 2025–12–14
four papers selected by
Irene Sambri, TIGEM

Autophagy Rep. 2025 ;4(1): 2596422

TFEB-mediated autophagy stimulation as an anabolic strategy for bone: insights from TFEB activation in the osteoblast lineage.

Melda Onal.

Autophagy in the osteoblast lineage is essential for bone formation and skeletal homeostasis, yet the mechanisms through which it supports bone formation remain unclear. To investigate these mechanisms and evaluate the anabolic potential of autophagy stimulation, we generated a genetic mouse model in which transcription factor EB (Tfeb), a master regulator of autophagy and lysosomal biogenesis, was elevated specifically in osteoblast-lineage cells. Tfeb elevation increased the expression of autophagy and lysosomal genes and enhanced autophagic flux in osteoblasts. Stimulation of autophagy increased bone formation in both cortical and cancellous bone compartments, leading to gains in bone mass and strength. Single-cell RNA sequencing revealed reduced osteoblast apoptosis, suggesting improved cell survival as a contributor to the observed increase in osteoblast number. Our ex vivo studies also suggest that autophagy stimulation increases proliferation of osteoblats lineage cells. In addition to increasing osteoblast number, Tfeb elevation also enhanced osteoblast function, likely by increasing transcription and translation of extracellular bone matrix components. Taken together, these findings demonstrate that elevation of Tfeb in the osteoblast lineage cells stimulates autophagy, promotes bone formation, and leads to increased bone mass and strength, supporting further investigation of TFEB or autophagy activation as a potential therapeutic strategy for osteoporosis.

Keywords: Autophagy; bone; bone anabolic; bone formation; osteoblast; osteoprogenitor TFEB

DOI: https://doi.org/10.1080/27694127.2025.2596422

Histopathology. 2026 Jan;88(1): 193-213

MiT family translocation carcinomas of the kidney and related entities.

Pedram Argani.

The MiT subfamily of transcription factors includes TFE3, TFEB, TFEC and MITF. Gene fusions involving two of these transcription factors have been well characterized in two subtypes of renal cell carcinoma (RCC): TFE3-rearranged RCC (also known as Xp11 translocation RCC) and TFEB-rearranged RCC (which typically harbour a t(6;11)(p21;q12) translocation). TFE3 and TFEB have overlapping functional activity, which explains why these two subtypes of translocation RCC have many morphologic similarities and express similar downstream targets. Therefore, these two neoplasms are grouped together under the heading of 'MiT family translocation RCC'. TFE3-rearranged PEComas and TFEB-amplified RCC are more recently described related neoplasms harbouring alterations in these same genes. This review summarizes our current knowledge of these molecularly defined neoplasms, and differential diagnostic considerations.

Keywords: TFE3; TFEB; renal cell carcinoma

DOI: https://doi.org/10.1111/his.15560

Cell Rep. 2025 Dec 10. pii: S2211-1247(25)01436-6. [Epub ahead of print]44(12): 116664

Neuronal hyperactivity becomes mTORC1 independent due to transcriptional changes in tuberous sclerosis complex disease models.

Wardiya Afshar-Saber, Juan F Ruiz, Isabel Gisser, Ziqin Yang, Leena Mehendale, Nicole A Teaney, Rachel Hobson, Madison R Glass, Truc T Pham, Elizabeth Bainbridge, Mustafa Sahin, Kellen D Winden.

Tuberous sclerosis complex (TSC) is caused by variants in either TSC1 or TSC2, which cooperate to inhibit the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with neurological disorders that are attributed to disinhibition of mTORC1, but the mechanisms connecting dysregulation of mTORC1 to molecular and physiological changes in neurons remain unclear. In this study, we aim to understand transcriptional changes in TSC and identify downregulation of the immediate-early gene EGR1 in TSC2-deficient excitatory neurons. Furthermore, we find that activity-dependent transcription is impaired in TSC due to abnormalities in maturation-dependent DNA demethylation. Finally, we determine that mTORC1 inhibition started late in neuronal maturation of human neurons is only partially effective in reversing gene expression changes and ineffective in reducing spontaneous neuronal hyperactivity in TSC. These data demonstrate a critical window in early brain development where mTORC1 dysregulation leads to transcriptional changes that contribute to persistent neuronal abnormalities.

Keywords: CP: molecular biology; CP: neuroscience; DNA methylation; activity-dependent transcription; mTOR complex 1; tuberous sclerosis complex

DOI: https://doi.org/10.1016/j.celrep.2025.116664

Front Genet. 2025 ;16 1694739

Mechanistic study of TFE3 breakage in TFE3-rearranged renal cell carcinoma: the perspective of non-canonical DNA structures and their stability.

Xiaopo Zhang, Qinshuang Dang, Xinghe Pan, Zhenggen Deng, Yanhao Xu, Weidong Gan, Hongqian Guo.

Background/Objectives: To address the unelucidated mechanisms of breakpoint formation in TFE3-rearranged renal cell carcinoma (TFE3-rRCC), this study characterizes breakpoint distribution within the TFE3 gene. We further explore how non-canonical DNA structures and their thermodynamic stability fluctuation may act as predisposing factors for the genomic instability driving these characteristic translocations.
Methods: TFE3 breakpoints were identified in a cohort of 31 TFE3-rRCC tumor samples. The chi-square test was used to assess the statistical significance of breakpoint clustering. To investigate potential structural determinants, we predicted the distribution of G-quadruplex-forming sequences and palindromic motifs. Moving beyond simple motif density, we calculated the local Gibbs free energy changes (ΔG) associated with DNA secondary structures using Mfold and RNAfold to model thermodynamic stability across the TFE3 gene. This thermodynamic stability fluctuation was quantified as the maximum absolute local change in folding free energy (|dΔG|). Finally, this correlation between thermodynamic stability fluctuation and breakpoint location was validated by analyzing the 13 most frequently rearranged genes reported in the COSMIC database.
Results: A significant breakpoint cluster was identified within intron 5 of TFE3, containing 23 of 31 breakpoints (74.19%; chi-square test, P < 0.05). While the simple density of G-quadruplex or palindromic motifs did not directly correlate with breakpoint locations, a strong association with local thermodynamic stability fluctuation was observed. The region within intron 5 exhibited the highest thermodynamic stability fluctuation. This result suggests that regions of high thermodynamic stability fluctuation are correlated with increased susceptibility to DNA breakage. This finding was corroborated in the COSMIC dataset, where breakpoints in 12 of the 13 most frequently rearranged genes were similarly located near peaks of high |dΔG|.
Conclusion: Our findings indicate that breakpoint events in TFE3-rRCC are non-randomly clustered within intron 5. This clustering correlates strongly with regions characterized by high thermodynamic stability fluctuation (|dΔG|) of potential non-canonical DNA secondary structures. The principle that elevated local thermodynamic stability fluctuation is a feature of breakpoint locations was supported by analysis of a broader set of oncogenes, suggesting that high local thermodynamic stability fluctuation is a common feature of translocation-prone regions in cancer, representing a plausible, though not proven, contributor to genomic fragility.

Keywords: TFE3-rearranged renal cell carcinoma; chromosome breakpoint; genome instability; gibbs free energy; non-canonical DNA structure

DOI: https://doi.org/10.3389/fgene.2025.1694739