Bess Frost

Exclusion of genomic “dark regions” from traditional DNA sequencing analysis limits our understanding of human biology and disease. These regions are highly repetitive, structurally complex, and lacking in the standard GRCh38 human reference genome. 2/9

Dark regions include low-complexity microsatellites, transposable element–rich sequences, and large ribosomal DNA arrays. 3/9

Long-read sequencing paired with the new telomere-to-telomere human reference genome overcomes these challenges. @nanoporetech.com sequencing also preserves native DNA modifications, enabling analysis of methylation in repetitive sequences. 4/9

Using Oxford Nanopore sequencing of DNA from early-stage AD, late-stage AD, and age-matched control brains, we find that repetitive segments of the genome are especially prone to genomic changes. 5/9

Putatively somatic retrotransposon insertions are concentrated in centromeric and pericentromeric regions in the aged brain. Ribosomal DNA arrays show a high frequency of non-allelic homologous recombination compared to other regions. 6/9

In Alzheimer’s disease, rare somatic retrotransposition events involving the SINE AluY family show a trending increase with advanced disease stage. Clear stage-specific patterns emerge in non-allelic homologous recombination and DNA methylation within repetitive elements. 7/9

This represents the first long-read analysis of retrotransposons, non-allelic homologous recombination, structural variants, and methylation in genomic dark regions of the aged human brain. Retrotransposons, centromeric regions, and rDNA are key hotspots of variation. 8/9

Thank you to our collaborators, the NIH, the Rainwater Foundation, and the BrightFocus Foundation for supporting this work. 9/9

Frost lab paper alert! This study was led by Dr. Paul Ramirez, Lead Biostatistician for the Brown University Center for Alzheimer’s Disease Research: alz-journals.onlinelibrary.wiley.com/doi/epdf/10.... 1/9

Cell autonomous microglia defects in a stem cell model of frontotemporal dementia tau - Molecular Psychiatry Molecular Psychiatry - Cell autonomous microglia defects in a stem cell model of frontotemporal dementia tau

Excited to share new work from the lab showing that FTD causing mutations in tau cause widespread defects in microglia function
www.nature.com/articles/s41...

I wasn’t even able to download the applications I’m supposed to review - I get an error message from the system.

Cells are subject to mechanical forces that shape their function and survival through a process termed “mechanotransduction.” While well studied outside of the brain, neuronal mechanotransduction is understudied despite exposure of the brain to vascular flow, injury, and disease.

2/9

Lamin Dysfunction Mediates Neurodegeneration in Tauopathies In this study, Frost et al. identify the lamin nucleoskeleton and improper cytoskeletal/nucleoskeletal coupling as novel mediators of neurotoxicity in tauopathies, including human Alzheimer’s disease....

This study was an outgrowth of our original finding that tau destabilizes the nucleoskeleton in neurons and drives nuclear envelope blebbing and invagination:
www.cell.com/current-biol...

3/9

Frontiers | Pathogenic tau decreases nuclear tension in cultured neurons Neurodegenerative tauopathies, including Alzheimer’s disease, are pathologically defined by the presence of aggregated forms of tau protein in brains of affe...

Claira subsequently discovered that nuclear tension is reduced in a cellular model of tauopathy:
www.frontiersin.org/journals/agi...

4/9

Led by proteomics, we now hone in on a specific protein, emerin, that is elevated in cell culture models of tauopathy. Emerin is a central regulator of nuclear mechanotransduction that allows cells to sense and respond to cellular force.

5/9

Claira finds that emerin overexpression in cultured neurons is sufficient to drive toxicity, increase filamentous actin, and induce nuclear invagination, cellular phenotypes that also occur in settings of tauopathy.

6/9

She further finds that emerin relocalizes from the nucleus to the cytosol in a cellular model of tauopathy, where it has increased interaction with cytoskeletal regulators.

7/9

Our findings lay the groundwork for future studies on the role of emerin and altered nuclear mechanotransduction in neurodegenerative tauopathies and highlight an emerging function of emerin as a regulator of nuclear mechanotransduction in neurons.

8/9

New Frost lab preprint from @SohnClaira: “Elevation of the mechanically-sensitive protein emerin links nuclear mechanotransduction to tau-induced cytoskeletal remodeling in neurons”

www.biorxiv.org/content/10.1...

1/9

It’s never too early. Just write the grant and see what you think. That’s when all the good ideas come anyway.

Interested in transcriptome complexity, RNA mods, polyA tail length, or retrotransposons? Are you a data junky who likes to mine new resources? Our Nanopore-based direct RNA sequencing study in Drosophila (in the context of health and #tau pathogenicity) is for you.
2/5

De novo transcriptome assembly reveals previously missed complexity, including abundant transcripts with retained introns. Transcripts with long polyA tails are enriched for signal transduction and MAPK signaling, while those with short polyA tails are enriched for translation/ATP metabolism.
3/5

We find that m6A modification is highly variable across transcripts, with enrichment at the 5'UTR and transcription start sites. Highly m6A-modified transcripts are associated with immune system processes, while those with lower m6A are associated with homeostatic translation.
4/5

We leverage long reads to map source loci for active retrotransposons, with copia elements showing particularly high m6A, then compare all these findings (m6A, polyA, retrotransposons, etc.) to a fly model of tauopathy. Check out the paper to see what intrigues you.
5/5

Long-read sequencing-based analyses of the adult Drosophila brain transcriptome in physiological and pathological settings - BMC Genomics Optimal brain function requires that neurons carry out extensive post-transcriptional RNA processing to produce a vast diversity of transcripts. Accurate reconstruction and quantification of highly pr...

New Frost Lab Paper/Dataset Alert! bmcgenomics.biomedcentral.com/articles/10....

Congrats to co-first authors @PaulRamirez42 and Dr. Gabbe Zuniga.

@carneyinstitute.bsky.social

1/5

While we are particularly interested in candidates who focus on cellular and molecular mechanisms driving neurodegeneration and/or specialize in human brain analyses, we encourage applicants from any research area that aligns with the mission of the center.

We promote discovery and innovation in neurodegenerative disorders by supporting a diverse community of experimentalists, theorists, engineers, and clinicians.

Our focus is to bridge the gap between scientific discovery and clinical application by uniting pioneering researchers with dedicated clinicians to accelerate the translation of discoveries into new diagnostic approaches and therapies.

We are excited to announce a new open search for a tenure track Assistant Professor position within the Brown University Center for Alzheimer's Disease Research!

Apply here: apply.interfolio.com/175427

A subset of transposable elements as mechano-response enhancer elements in controlling human embryonic stem cell fate - Nature Cell Biology Sun et al. identify a subset of transposable elements that serve as mechano-response enhancer elements that control gene expression and human stem cell fate.

💫NEW: Sun et al. identify a subset of transposable elements that serve as mechano-response enhancer elements that control #GeneExpression and human #StemCell fate.
👉https://rdcu.be/eJqGP
bit.ly/4gYgJjm