Bess Frost
@bessfrost.bsky.social
Salame-Feraud Director, Center for Alzheimer’s Disease Research | Brown University
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
November 14, 2025 at 5:09 PM
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
November 14, 2025 at 5:09 PM
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
November 14, 2025 at 5:09 PM
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
November 14, 2025 at 5:08 PM
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
November 14, 2025 at 5:08 PM
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
November 14, 2025 at 5:08 PM
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
November 14, 2025 at 5:08 PM
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
November 14, 2025 at 5:07 PM
Thank you to our collaborators, the NIH, the Rainwater Foundation, and the BrightFocus Foundation for supporting this work. 9/9
I wasn’t even able to download the applications I’m supposed to review - I get an error message from the system.
October 21, 2025 at 9:51 AM
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.
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2/9
October 20, 2025 at 7:04 PM
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
2/9
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
www.cell.com/current-biol...
3/9
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....
www.cell.com
October 20, 2025 at 7:04 PM
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
www.cell.com/current-biol...
3/9
Claira subsequently discovered that nuclear tension is reduced in a cellular model of tauopathy:
www.frontiersin.org/journals/agi...
4/9
www.frontiersin.org/journals/agi...
4/9
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...
www.frontiersin.org
October 20, 2025 at 7:04 PM
Claira subsequently discovered that nuclear tension is reduced in a cellular model of tauopathy:
www.frontiersin.org/journals/agi...
4/9
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
5/9
October 20, 2025 at 7:03 PM
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
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
6/9
October 20, 2025 at 7:03 PM
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
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
7/9
October 20, 2025 at 7:03 PM
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
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
8/9
October 20, 2025 at 7:02 PM
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
8/9
It’s never too early. Just write the grant and see what you think. That’s when all the good ideas come anyway.
October 16, 2025 at 12:59 AM
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
2/5
October 15, 2025 at 3:28 PM
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
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
3/5
October 15, 2025 at 3:27 PM
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
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
4/5
October 15, 2025 at 3:27 PM
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
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
5/5
October 15, 2025 at 3:25 PM
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
5/5