Disrupted methionine cycle triggers muscle atrophy in cancer cachexia through epigenetic regulation of REDD1.

The essential amino acid methionine plays a pivotal role in one-carbon metabolism, facilitating the production of S-adenosylmethionine (SAM), a critical supplier for DNA methylation and thereby a modulator of gene expression. Here, we report that the methionine cycle is disrupted in skeletal muscle during cancer cachexia, leading to endoplasmic reticulum stress and DNA hypomethylation-induced expression of the DNA damage inducible transcript 4 (Ddit4) gene, encoding the regulated in development and DNA damage response 1 (REDD1) protein. Targeting DNA methylation by depletion or pharmacological inhibition of DNA methyltransferase 3A (DNMT3A) exacerbates cachexia, while restoring DNMT3A expression or REDD1 knockout alleviates cancer cachexia-induced skeletal muscle atrophy in mice.

Reprogramming of the LXRα Transcriptome Sustains Macrophage Secondary Inflammatory Responses.

Macrophages regulate essential aspects of innate immunity against pathogens. In response to microbial components, macrophages activate primary and secondary inflammatory gene programs crucial for host defense. The liver X receptors (LXRα, LXRβ) are ligand-dependent nuclear receptors that direct gene expression important for cholesterol metabolism and inflammation, but little is known about the individual roles of LXRα and LXRβ in antimicrobial responses.

Transcriptional determinants of lipid mobilization in human adipocytes.

Defects in adipocyte lipolysis drive multiple aspects of cardiometabolic disease, but the transcriptional framework controlling this process has not been established. To address this, we performed a targeted perturbation screen in primary human adipocytes. Our analyses identified 37 transcriptional regulators of lipid mobilization, which we classified as (i) transcription factors, (ii) histone chaperones, and (iii) mRNA processing proteins.

Antioxidants stimulate BACH1-dependent tumor angiogenesis.

Lung cancer progression relies on angiogenesis, which is a response to hypoxia typically coordinated by hypoxia-inducible transcription factors (HIFs), but growing evidence indicates that transcriptional programs beyond HIFs control tumor angiogenesis. Here, we show that the redox-sensitive transcription factor BTB and CNC homology 1 (BACH1) controls the transcription of a broad range of angiogenesis genes. BACH1 is stabilized by lowering ROS levels; consequently, angiogenesis gene expression in lung cancer cells, tumor organoids, and xenograft tumors increased substantially following administration of vitamins C and E and N-acetylcysteine in a BACH1-dependent fashion under normoxia.