Induction of Fatty Acid Oxidation Underlies DNA Damage-Induced Cell Death and Ameliorates Obesity-Driven Chemoresistance.

The DNA damage response is essential for preserving genome integrity and eliminating damaged cells. Although cellular metabolism plays a central role in cell fate decision between proliferation, survival, or death, the metabolic response to DNA damage remains largely obscure. Here, this work shows that DNA damage induces fatty acid oxidation (FAO), which is required for DNA damage-induced cell death. Mechanistically, FAO induction increases cellular acetyl-CoA levels and promotes N-alpha-acetylation of caspase-2, leading to cell death. Whereas chemotherapy increases FAO related genes through peroxisome proliferator-activated receptor α (PPARα), accelerated hypoxia-inducible factor-1α stabilization by tumor cells in obese mice impedes the upregulation of FAO, which contributes to its chemoresistance. Finally, this work finds that improving FAO by PPARα activation ameliorates obesity-driven chemoresistance and enhances the outcomes of chemotherapy in obese mice. These findings reveal the shift toward FAO induction is an important metabolic response to DNA damage and may provide effective therapeutic strategies for cancer patients with obesity.

Unveiling the enigma of Brain-resident immune cells.

The immune system has been extensively studied in traditional immune hubs like the spleen and lymph nodes. However, recent advances in immunology highlight unique immune cell characteristics across anatomical compartments. In this study, we challenged conventional thinking by uncovering distinct immune cell populations within the brain parenchyma, separate from those in the blood, meninges, and choroid plexus, with unique transcriptional profiles. Brain-resident immune cells are not derived from maternal immune cells, and age-related changes, with an increase in CD8 + T cells in aged mice, are noted. Alzheimer's disease (AD) alters microglia's interaction with brain-resident immune cells, emphasizing immune-brain dynamics. Furthermore, we reveal dynamic immune cell interactions and essential cytokine roles in brain homeostasis, with stable cytokine expression but emerging signaling pathways in AD. In summary, this study advances our understanding of brain-resident immune cells in both normal and pathological conditions.

Heterogeneity is not always a source of noise: Stochastic gene expression in regulatory heterozygote.

Zygosity of diploid genome (i.e., degree to which two parental alleles of a gene have varied genetic sequences) adds another dimension to stochastic gene expression. The allelic imbalance in chromatin accessibility or divergence in regulatory sequences leads to fitness effects but the quantitative aspects thereof are largely left unexplored. We investigate diploid gene expression systems with homozygous (the same) and heterozygous (varied) combination of alleles in cis-regulatory sequences, not in structural gene loci, and characterize the zygosity-associated stochastic fluctuations in protein abundance. An emerging feat of heterozygosity is its counterintuitive capacity for genetic noise control. Especially when the noise is dominantly contributed to by the fluctuations in duty cycle ("reliability") rather than in process speed ("productivity") of gene expression machinery, its interallelic discrepancy acts to reduce the gene expression noise. These findings offer a novel insight into the rich repertoire of balancing selection enriched in the regulatory elements of immune response genes.

Selected heterozygosity at cis-regulatory sequences increases the expression homogeneity of a cell population in humans.

BACKGROUND: Examples of heterozygote advantage in humans are scarce and limited to protein-coding sequences. Here, we attempt a genome-wide functional inference of advantageous heterozygosity at cis-regulatory regions. RESULTS: The single-nucleotide polymorphisms bearing the signatures of balancing selection are enriched in active cis-regulatory regions of immune cells and epithelial cells, the latter of which provide barrier function and innate immunity. Examples associated with ancient trans-specific balancing selection are also discovered. Allelic imbalance in chromatin accessibility and divergence in transcription factor motif sequences indicate that these balanced polymorphisms cause distinct regulatory variation. However, a majority of these variants show no association with the expression level of the target gene. Instead, single-cell experimental data for gene expression and chromatin accessibility demonstrate that heterozygous sequences can lower cell-to-cell variability in proportion to selection strengths. This negative correlation is more pronounced for highly expressed genes and consistently observed when using different data and methods. Based on mathematical modeling, we hypothesize that extrinsic noise from fluctuations in transcription factor activity may be amplified in homozygotes, whereas it is buffered in heterozygotes. While high expression levels are coupled with intrinsic noise reduction, regulatory heterozygosity can contribute to the suppression of extrinsic noise. CONCLUSIONS: This mechanism may confer a selective advantage by increasing cell population homogeneity and thereby enhancing the collective action of the cells, especially of those involved in the defense systems in humans.