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PNAS Papers on Age-Related Macular Degeneration Locus, Exhausted CAR T Cells, More

Editor's Note: Some of the articles described below are not yet available at the PNAS site, but they are scheduled to be posted this week.

A team from the University of Utah digs into a chromosome 10 locus linked to age-related macular degeneration (AMD) in past genome-wide association studies, detecting lower-than-usual levels of one of the genes at this locus in an AMD-related tissue type. Using array-based genotyping, qRT-PCR, chromatin immunoprecipitation sequencing, and other approaches, the researchers compared the expression of the chromosome 10q26 genes ARMS2 and HTRA1 in post-mortem samples from individuals with or without heterozygous or homozygous copies of AMD-related alleles at 10q26, detecting reduced HTRA1 expression in retinal pigment epithelium (RPE) tissue that appeared to stem from changes in the gene's regulatory region. The authors note that "HtrA1 protein levels increase significantly with age in the RPE-choroid of homozygous non-risk donors and the HRA1 [messenger RNA] protein expression is reduced in the RPE of homozygous risk donors relative to homozygous non-risk donors." Even so, they add, "[r]educed expression of HTRA1 occurred in RPE tissues from donors without AMD, suggesting that this is an early event in the disease process."

Researchers at Stanford University and elsewhere explore the epigenetic, enhancer, and expression features linked to human chimeric antigen receptor T cell (CAR T) exhaustion. The team relied on RNA sequencing, Omni-ATAC-seq, Hi-C with chromatin immunoprecipitation, and other methods to characterize gene regulatory features in exhaustion-prone and non-exhausted CAR T cells, focusing in on chromatin accessibility and chromosome conformation shifts that occurred in advance of exhaustion-related expression changes. "As the genetic networks underlying the T cell response to antigen and T cell exhaustion are largely independent, we can dissect the uniquely exhaustion-associated network and uncover co-regulated modules of accessible chromatin loci, transcription factors, and dysregulated genes," the authors say. "The genomic features we identify may be used to inform targeted genomic studies using CRISPR-Cas9 to restrict expression of exhaustion markers such that the ex vivo maturation of CAR T cells does not induce T cell exhaustion prior to transfusion."

Investigators in the US and Germany describe a rise in the rate of mitochondrial DNA (mtDNA) heteroplasmies in lymphoblast samples from individuals with Huntington's disease. With the help of a targeted mtDNA sequencing strategy, the team compared lymphoblast and blood samples from 1,549 Huntington's disease patients and 182 unaffected control individuals, uncovering apparent expansions of heteroplasmic mitochondrial oxidative phosphorylation-related sequences in individuals with the neurodegenerative condition. Additional data collected from another 169 Huntington's disease patients over several years suggest that these expansions tend to track with diminished motor function and more advanced cognitive symptoms, the authors note. "The results of our study indicate accelerated decline of mtDNA quality in [Huntington's disease]," they write, "and highlight monitoring mtDNA heteroplasmies longitudinally as a way to investigate the progressive decline of mitochondrial function in aging and age-related diseases."

The Scan

Panel Votes for COVID-19 Pill

A US Food and Drug Administration panel has voted to support the emergency use authorization of an antiviral pill for COVID-19 from Merck and Ridgeback Biotherapeutics, CNN says.

But Not Harm

New Scientist reports that UK bioethicists say that though gene editing may improve food production, it should not harm livestock welfare.

Effectiveness Drop Anticipated

Moderna's Stéphane Bancel predicts that that current SARS-CoV-2 vaccines may be less effective against the Omicron variant, the Financial Times reports.

Cell Studies of Human Chromatin Accessibility, SARS-CoV-2 Variants, Cell Signaling Networks

In Cell this week: chromatin accessibility maps of adult human tissues, modeling to track SARS-CoV-2 variants of concern, and more.