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PNAS Studies on ER+ Breast Cancer Target, Skin Condition Gene Repair, Uveoretinitis

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

A Baylor College of Medicine-led team explores the consequences of FOXA1 upregulation in estrogen receptor (ER)-positive, metastatic breast cancer cases that are resistant to endocrine therapy. By bringing together RNA sequence, transcription factor chromatin immunoprecipitation sequencing, and other data for ER-resistant breast cancer cell lines, the researchers uncovered super-enhancer-regulated enhancer reprogramming, including a HIF-2-alpha transcription factor induced by FOXA1. Their follow-up analyses suggest the increased FOXA1-HIF-2-alpha activity is typically found in ER-positive cases missing ESR1 mutations, and may be susceptible to a selective HIF-2-alpha inhibitor being tested in other cancer types. "These findings demonstrate the role of FOXA1 upregulation in enhancer reprogramming and a therapeutic approach of targeting deregulated transcriptional programs to circumvent endocrine-resistant metastatic [breast cancer]," they say.

Researchers from the US, Japan, and Mexico demonstrate that it may be possible to correct the COL7A1 collagen gene mutations behind an inherited skin condition called recessive dystrophic epidermolysis bullosa (RDEB) in mice using gene editing, induced pluripotent stem cell (iPSC) differentiation, and skin grafting. The team began by designing CRISPR-Cas9 guide RNAs to target two mutations in exons 19 and 32 of COL7A1, using the approach to edit mutations affecting one or both versions of the gene in iPSCs, which were subsequently differentiated into keratinocyte and fibroblast cells that were grafted onto mice. "Safety assessment for potential off-target Cas9 cleavage activity did not reveal any unintended nuclease activity," the authors report, noting that the results "represent a crucial advance for clinical applications of innovative autologous stem cell-based therapies for RDEB."

Using single-cell RNA sequencing, a team from Johns Hopkins takes a look at a mouse model of "spontaneous, chronic, and progressive" uveoretinitis, an inflammatory autoimmune condition that affects the retina and leads to vision loss. Using immunostaining, in situ hybridization, and droplet-based scRNA-seq data for almost 64,200 individual retina cells from aging mouse models with or without the Aire gene — which codes for a uveoretinitis-related transcription factor that regulates a number of retinal antigens — the researchers defined expression-based cell clusters in the retina and tracked immune cell activity in the uveoretinitis-affected tissues. Together, they report, results from the study suggest "ocular inflammation is context-specific in terms of the molecular mechanisms and immune cell types involved."

The Scan

Could Mix It Up

The US Food and Drug Administration is considering a plan that would allow for the mixing-and-matching of SARS-CoV-2 vaccines and boosters, the New York Times says.

Closest to the Dog

New Scientist reports that extinct Japanese wolf appears to be the closest known wild relative of dogs.

Offer to Come Back

The Knoxville News Sentinel reports that the University of Tennessee is offering Anming Hu, a professor who was acquitted of charges that he hid ties to China, his position back.

PNAS Papers on Myeloid Differentiation MicroRNAs, Urinary Exosomes, Maize Domestication

In PNAS this week: role of microRNAs in myeloid differentiation, exosomes in urine, and more.