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.
In a paper scheduled to appear in PNAS this week, Leiden University Medical Center researchers explore the consequences of premature termination codons in DMD, a dystrophin-coding gene affected by rare mutations in individuals with Duchenne muscular dystrophy. Using RNA sequencing, qPCR, and other experiments in mouse models with a nonsense DMD gene mutation, the team showed that interfering with nonsense-mediated decay machinery did not restore DMD levels, which are typically lower-than-usual when premature termination codons are present. Based on results from follow-up RNA-seq, chromatin immunoprecipitation, and other analyses in mice, the authors suggest that premature termination codons may instead curb DMD expression by altering gene regulation and transcription of the gene. "Analysis of nascent RNA and histone marks shows that transcription is less efficient in the presence of premature termination codons," they report, noting that "[t]reatment of dystrophic mice with an epigenetic drug, currently in clinical development, partially restores transcription of the locus."
A team from Canada, Japan, and the US describe an approach for knocking down the DUX4 gene in muscle with an eye to treating a progressive, inherited muscle weakness condition called facioscapulohumeral muscular dystrophy (FSHD), which involves altered muscle expression of the gene. The researchers relied on antisense oligonucleotide-based gene knockdown with so-called locked nucleic acid (LNA) gapmers, narrowing in on gapmers that appeared to dial down DUK4 levels specifically in mouse models of FSHD and in patient-derived muscle cell lines. "Taken together," they say, "we expect the promising therapeutic we have developed and the [antisense oligonucleotide] screening method used in this study to facilitate progress in the field toward the production of viable treatments for FSHD."
Researchers at Dana-Farber Cancer Institute and elsewhere report on a transcriptional regulation role for the neuroblastoma-related gene LIN28B that appears to be distinct from its regulatory interactions with let-7, which blocks precursor microRNA processing and inhibits related miRNA biogenesis. Results from the team's cell line, chromatin immunoprecipitation sequencing and co-immunoprecipitation experiments suggest that versions of LIN28B that lack the ability to process let-7 can still boost neuroblastoma migration and progression via interactions with the ZNF143 transcription factor that boost the expression of downstream pathways exploited by the peripheral sympathetic nervous system tumors. "[W]e show that LIN28B is recruited to active promoters by binding to the zinc-finger transcription factor ZNF143," the authors say, calling LIN28B "a co-factor to upregulate expression of a subset of downstream target genes that are essential for neuroblastoma cell survival and migration."