Base by Base

Han et al., Nature Communications - This study uses paired single-nucleus chromatin accessibility and gene expression profiling across Alzheimer’s disease, Pick’s disease and progressive supranuclear palsy to map disease-dynamic cis-regulatory elements (CREs). Dynamic chromatin changes concentrate genetic risk in glial cell states and co-regulated regulatory modules. Integrating GWAS, sn-eQTLs and MPRA validates functional noncoding variants that tune lysosomal, lipid and vesicular pathways. Experimental CRISPRa and histology support a stress-inducible SOX10-driven glial program linked to resilience. Key terms: snATAC-seq, tauopathies, microglia, chromatin accessibility, SOX10.

Study Highlights:
The authors profiled matched snATAC-seq and snRNA-seq from three brain regions across AD, PiD and PSP and defined cell-type-specific CREs and 50 subclusters. Disease-dynamic peaks concentrated in glia and disproportionately capture GWAS heritability, with PiD-linked mg.C4 microglia and PSP-linked ast.C1 astrocytes identified as risk-associated states. MPRA in microglial models and sn-eQTL integration validated functional regulatory variants that converge on MEF2C/SOX10 and SNARE-centered modules affecting lysosomal, sphingolipid and trafficking pathways. CRISPRa induction of SOX10 in iPSC-derived microglia under synaptosome stress recapitulated mg.C4 programs, and RNAscope/IHC confirmed SOX10+/PLP1+ glial states in human tissue.

Conclusion:
Dynamic, disease-context-specific chromatin remodeling in glia concentrates genetic risk into co-regulated regulatory modules that modulate lysosomal, lipid and vesicular pathways; these modules nominate SOX10-, MEF2- and SNARE-centered circuits as candidate modulators of glial resilience across tauopathies.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states

First author:
Han

Journal:
Nature Communications

DOI:
10.1038/s41467-026-73007-1

Reference:
Han, X., Rosenberg, G.M., Kisling, V.M. et al. Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73007-1

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/epigenomic-glial-genetic-risk-tauopathies

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-19.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript portions describing glial states mg.C4 microglia and ast.C1 astrocytes, regulatory networks (MEF2C/MEF2D), SOX10's role and ectopic expression, MPRA validation, CRISPRaSOX10 experiments, dynamic CREs and heritability findings, and study limitations.
- transcript topics: Glial states mg.C4 microglia and ast.C1 astrocytes across tauopathies; MEF2C/MEF2D regulatory modules linking to lysosomal and phagocytic pathways; SOX10 as a stress-responsive regulator and ectopic expression in glia; MPRA validation of regulatory variants in microglia (frVars); CRISPRa SOX10 activation in hiPSC-derived microglia and recapitulation of mg.C4 programs; Dynamic CREs and GWAS heritability enrichment across disorders

Yang X et al., Proceedings of the National Academy of Sciences - Genetic and pharmacologic inhibition of ICMT suppresses proliferation, invasion, and tumor growth in BRAFV600E-driven models and identifies INPP5E as an ICMT-dependent CAAX substrate whose membrane targeting supports melanoma growth. Key terms: ICMT, INPP5E, BRAFV600E, melanoma, UCM-1336.

Study Highlights:
ICMT genetic knockdown or pharmacologic inhibition (UCM-1336) reduced proliferation and invasion of BRAFV600E-mutant melanoma cells, decreased tumor growth in xenografts and mouse models, and retained activity in BRAF-inhibitor-resistant cells. ICMT inhibition reduced INPP5E carboxyl methylation, displaced INPP5E from membranes to the cytosol, and increased cellular PI(4,5)P2. Forced membrane targeting of INPP5E (Lyn-INPP5E) partially rescued proliferation and tumor growth during ICMT suppression. These results implicate an ICMT–INPP5E axis that supports BRAFV600E-driven tumor growth without measurable suppression of MAPK signaling.

Conclusion:
ICMT-dependent methylation and membrane targeting of INPP5E contribute to BRAFV600E-driven tumor growth, and ICMT inhibition (genetic or with UCM-1336) impairs melanoma growth including in BRAF-inhibitor-resistant models, highlighting ICMT as a context-dependent therapeutic vulnerability.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
ICMT supports BRAF
V600E
-driven tumor growth by membrane targeting of the CAAX protein INPP5E

First author:
Yang X

Journal:
Proceedings of the National Academy of Sciences

DOI:
10.1073/pnas.2601795123

Reference:
Yang X, Qiao X, Schmidt S, et al. ICMT supports BRAFV600E-driven tumor growth by membrane targeting of the CAAX protein INPP5E. PNAS. 2026;123(20):e2601795123. doi:10.1073/pnas.2601795123

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/icmt-inpp5e-brafv600e-membrane-targeting

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-18.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited sections describing ICMT/CAAX processing, INPP5E as an ICMT substrate, membrane targeting and PI(4,5)P2 effects, rescue experiments, in vitro/in vivo models, and therapeutic implications.
- transcript topics: ICMT and CAAX protein processing; INPP5E as an ICMT substrate and its membrane localization; Impact of ICMT inhibition on BRAFV600E melanoma cell proliferation and invasion; MAPK signaling independence from ICMT inhibition; In vivo models and genetic/pharmacologic ICMT suppression; Rescue experiments with Lyn-INPP5E and rescue implications

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- ICMT inhibition reduces BRAFV600E-driven melanoma cell proliferation and invasion in vitro and tumor growth in vivo.
- INPP5E is an ICMT-dependent CAAX substrate; ICMT inhibition reduces INPP5E methylation and displaces it from membranes.
- Displa...

White MC et al., PNAS - This episode reviews a PNAS study showing that the kinase NEK2 is upregulated by EBV and its latency proteins and that NEK2 inhibition with the irreversible inhibitor JH295 selectively kills EBV-positive non-Hodgkin lymphoma cells, lowers drug resistance, and reduces tumor burden in mouse models. Key terms: NEK2, EBV, non-Hodgkin lymphoma, LMP1, drug resistance.

Study Highlights:
EBV infection and the latency proteins EBNA1, LMP1, and EBNA2 increase NEK2 expression in human B cells and patient tumors. Genetic depletion or pharmacologic inhibition of NEK2 with JH295 selectively kills EBV-positive NHL cells and induces inflammatory, ROS-associated cell death with gasdermin D cleavage. NEK2 inhibition reduces LMP1 and c-myc expression, decreases ABC transporter expression and MRP1-mediated drug efflux, and sensitizes cells to doxorubicin. In xenograft and cord blood-humanized mouse models JH295 lowered tumor burden, reduced tumor incidence, and prolonged survival without observable toxicity.

Conclusion:
NEK2 is a promising therapeutic target in EBV-positive non-Hodgkin lymphoma; NEK2 inhibition by JH295 both kills malignant cells and reduces drug resistance and viral oncoprotein expression in preclinical models.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
NEK2 drives pathogenesis, drug resistance, and LMP1 expression in EBV-positive non-Hodgkin lymphoma

First author:
White MC

Journal:
PNAS

DOI:
10.1073/pnas.2535550123

Reference:
White MC, Lange PT, Stewart J, Damania B. NEK2 drives pathogenesis, drug resistance, and LMP1 expression in EBV-positive non-Hodgkin lymphoma. Proc Natl Acad Sci U S A. 2026;123:e2535550123. doi:10.1073/pnas.2535550123

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/nek2-drives-ebv-positive-nhl

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-16.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript passages on EBV-induced NEK2 upregulation, NEK2 inhibition mechanisms (ROS, gasdermin D), downstream effects (LMP1, c-Myc, beta-catenin, Bcl-2 family), MRP1/ABC transporters and drug resistance, and in vivo xenograft and cord blood–humanized mouse results.
- transcript topics: EBV-induced NEK2 upregulation in primary B cells; EBV latency proteins EBNA1, LMP1, EBNA2 drive NEK2 expression; JH295 NEK2 inhibitor and EBV+ NHL selectivity; Inflammatory cell death: ROS accumulation and gasdermin D cleavage; Downregulation of LMP1, c-Myc, beta-catenin; Bcl-2 family modulation; MRP1/MDR transporters and drug resistance reversal

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- EBV latency proteins EBNA1, LMP1, EBNA2 independently drive NEK2 upregulation
- Primary EBV infection increases NEK2 expression in human B cells
- NEK2 inhibition with JH295 induces inflammatory, ROS-associated cell death with gasdermin D cleavage in EBV-positi...

Jhaldiyal A et al., PNAS - This episode summarizes a PNAS study showing that PARP1 activation links Aβ1-42 toxicity to DNA damage, amyloid accumulation, neuroinflammation, and cognitive deficits, and that genetic or pharmacologic PARP1 suppression reduces pathology in cells and 5XFAD mice. Key terms: PARP1, poly(ADP-ribose), Alzheimer's disease, amyloid beta, neurodegeneration.

Study Highlights:
CSF poly(ADP-ribose) (PAR) is elevated in patients with MCI and AD and negatively correlates with the Aβ42/40 ratio. Oligomeric Aβ1-42 activates PARP1 in primary cortical neurons, causing DNA damage and cell death that are prevented by PARP1 inhibitors or PARP1 genetic deletion. In 5XFAD mice, PARP1 knockout halves plaque burden, preserves synapses and neurons, reduces glial activation and inflammatory gene expression, and rescues spatial learning and memory. Mechanistically, PARP1 deficiency lowers BACE1, alters γ-secretase subunits (PSEN1 up, nicastrin down), and increases the Aβ-degrading enzyme NEP2.

Conclusion:
PARP1 is a critical mediator of Aβ-driven toxicity, amyloid accumulation, neuroinflammation, and cognitive decline in a familial AD model, and its inhibition may be a promising disease-modifying strategy.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
PARP1 deficiency mitigates amyloid pathology, neurodegeneration, and cognitive decline in a familial Alzheimer’s disease model

First author:
Jhaldiyal A

Journal:
PNAS

DOI:
10.1073/pnas.2525028123

Reference:
Jhaldiyal A., Kumari M., Guttman L. C., et al. PARP1 deficiency mitigates amyloid pathology, neurodegeneration, and cognitive decline in a familial Alzheimer’s disease model. PNAS (2026). DOI: 10.1073/pnas.2525028123

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/parp1-amyloid-neurodegeneration-5xfad

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-16.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing CSF PAR elevation, Aβ42-induced PARP1 activation in neurons, in vitro neuroprotection by PARP inhibitors, in vivo 5XFAD/PARP1−/− outcomes (plaque burden, neuronal survival, gliosis, cognitive tests), APP metabolism changes, NEP2 involvement, inflammation, and translational cav
- transcript topics: CSF PAR elevation in MCI and AD and relation to Aβ42/40; Oligomeric Aβ42 activates PARP1 and induces DNA damage; Pharmacologic/genetic PARP1 inhibition confers neuroprotection in vitro; 5XFAD/PARP1−/− mice: reduced amyloid plaque burden and neuronal loss; APP processing changes: BACE1 reduction, PSEN1/nicastrin alterations, NEP2 up; Neuroinflammation and gliosis attenuation with PARP1 loss

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- CSF PAR levels are elevated in MCI and AD and inversely correlate with the Aβ42/40 ratio
- Oligomeric Aβ1-42 activates PARP1 and induces DNA damage; PARP1 inhibition...

Singh P et al., PNAS - This paper compares alternative splicing (AS) and gene expression (GE) across 200 transcriptomes from oral and pharyngeal jaws of 18 haplochromine cichlid species across Lakes Victoria, Malawi, and Tanganyika. The authors show that rapid changes in AS, often from low-frequency ancestral isoforms and some novel isoforms, contributed more to early trophic diversification than shifts in GE. Key terms: alternative splicing, adaptive radiation, cichlids, gene regulation, craniofacial development.

Study Highlights:
Using 200 jaw transcriptomes spanning three East African cichlid radiations, the authors found that alternative splicing (AS) diverged faster than gene expression (GE) and was enriched for craniofacial and jaw morphogenesis genes. Most adaptive isoforms were present at low levels in nonradiating ancestral lineages and increased in frequency in radiating lineages, consistent with standing splice variation fueling rapid adaptation. A subset of novel isoforms evolved rapidly, some within a few thousand years, and mapped to candidate craniofacial genes such as col21a1. Younger radiations (Victoria, Malawi) showed stronger AS divergence while the older Tanganyika radiation displayed more GE differences.

Conclusion:
Ancestral alternative splice variation, supplemented by rapidly evolved novel isoforms, provided a labile reservoir of protein-coding diversity that likely enabled the extremely rapid trophic diversification of African cichlid radiations; integrating splicing into regulatory perspectives is essential to understand rapid adaptive evolution.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Ancestral splice variation is a key substrate for rapid diversification in African cichlids

First author:
Singh P

Journal:
PNAS

DOI:
10.1073/pnas.2516477123

Reference:
Singh P., Ahi E.P., Duenser A., Durdevic M., Gessl W., Schaeffer S., Gall J., Seehausen O., Sturmbauer C. Ancestral splice variation is a key substrate for rapid diversification in African cichlids. PNAS. 2026;123(20):e2516477123. doi:10.1073/pnas.2516477123

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/ancestral-splice-variation-african-cichlids

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-15.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing AS vs GE dynamics, ancestral standing variation, novel isoforms (col21a1), lake-by-lake evolutionary patterns, and convergent/trophic evolution; cross-checked against the original article.
- transcript topics: Adaptive radiation and jaw anatomy in African cichlids; Gene expression vs alternative splicing (GE vs AS); Ancestral standing variation and novel isoforms; Temporal patterns: young vs old radiations (Victoria/Malawi vs Tanganyika); Key genes: col21a1 and craniofacial pathways; Convergent vs divergent regulation across radiations

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article...