Biology subjects

Young, J. T.

Publications and source records attributed to Young, J. T..

5 recordsLinked to original sources

bioRxiv2026

Histone H4 acetyl-methyllysine marks accessible chromatin that resists compaction

Certain regulatory DNA regions remain accessible even under conditions of widespread chromatin compaction. These regions are often marked by specific protein factors and histone modifications that help maintain their accessibility. Here, we examine the genomic landscape of acetyl-methyllysine (Kacme), a recently discovered histone post-translational modification. Across multiple systems, Kacme is highly enriched at sites of accessible chromatin, including active promoters, enhancers, silencers, and CTCF-binding sites. We find that Kacme is selectively retained at loci that resist condensation during mitosis, marks XIST and escapee regions on the inactive X chromosome in female cells and demarcates the boundaries of broad heterochromatin domains. Kacme-marked insulator elements block heterochromatin spreading and protect adjacent genes from transcriptional repression, even when H3K27me3 levels are pharmacologically elevated through KDM6A/6B inhibition. Taken together, our findings establish the chromatin features associated with Kacme and support a model in which Kacme helps safeguard chromatin accessibility at loci that resist compaction.

molecular biology↗

bioRxiv2026

CRISPR-enabled genetic screens identify synthetic lethal targets across frequently altered cancer drivers

Synthetic lethality (SL) provides a treatment paradigm for targeting cancer with alterations in driver genes that are not conventionally druggable, including loss-of-function (LoF) mutations in tumor suppressor genes and gain-of-function (GoF) alterations in oncogenes. We undertook a series of genome-wide CRISPR screens using functionally validated isogenic cell lines and also conducted a large-scale SL analysis using data from the cancer dependency map (DepMap). We charted SL interactions across 15 genetic alterations characteristic of diseases with high incidence and unmet clinical need: FBXW7, CCNE1, CDK12, ARID1A, KMT2D, DNMT3A, TET2, KEAP1, STK11, IDH1, SF3B1, SRSF2, U2AF1, chromosome 18q loss, and chromosome 13q loss. We show validation of several SL interactions between tractable targets with cancer drivers, including ARID1A and the hexosamine biosynthetic pathway aminotransferase GFPT1, STK11 with CAMK protein kinase family members including MARK2, FBXW7 and the CDK1 regulatory kinase PKMYT1, and CCNE1 amplification and the anaphase promoting complex or cyclosome (APC/C). In summary, this study offers a rich resource of genetic interactions across cancer drivers enabling the discovery of new biological insights and drug targets for future therapeutic development.

cancer biology↗

bioRxiv2026

Anticipating on-target resistance to WRN inhibitors in microsatellite unstable cancers

Leveraging WRN helicase dependency in microsatellite instability (MSI) cancers offers a synthetic lethal (SL) therapeutic opportunity, with several WRN inhibitors in development. However, the hypermutator nature of MSI tumors creates strong evolutionary pressure for rapid resistance. Here, we apply a multimodal functional genomics framework integrating base editing screens and deep mutational scanning to map on-target resistance to two clinical WRN inhibitors, HRO761 and VVD-214. We identify discrete resistance hotspots within WRN and demonstrate that single-allele (heterozygous) mutations at the drug-binding site are sufficient to abrogate WRN inhibitor-induced cytotoxicity. Resistance profiles diverged between HRO761 and VVD-214, revealing mutations that impair one but preserve sensitivity to the other. Genome-wide CRISPR screens further identified non-homologous end joining (NHEJ) factors and the checkpoint phosphatase WIP1 as tractable synthetic vulnerabilities that potentiate WRN inhibition. Together, these findings establish a framework for resistance-aware deployment of WRN inhibitors through rational drug selection, therapeutic switching, and combination strategies. Statement of SignificanceResistance to WRN inhibitors threatens the clinical durability of synthetic lethal therapies in microsatellite-instable cancers. Using multimodal functional genomics, we identify predictable, drug-specific on-target resistance mechanisms and reveal DNA-PK as a tractable combination partner. These findings provide a framework for resistance-aware deployment of WRN inhibitors to improve therapeutic durability.

cancer biology↗

bioRxiv2024

Profound synthetic lethality between SMARCAL1 and FANCM

DNA replication stress is a threat to genome integrity. The large SNF2-family of ATPases participates in preventing and mitigating DNA replication stress by employing their ATP-driven motor to remodel DNA or DNA-bound proteins. To understand the contribution of these ATPases in genome maintenance, we undertook CRISPR-based synthetic lethality screens with three SNF2-type ATPases: SMARCAL1, ZRANB3 and HLTF. Here we show that SMARCAL1 displays a profound synthetic lethal interaction with FANCM, another ATP-dependent translocase involved in DNA replication and genome stability. Their combined loss causes severe genome instability that we link to chromosome breakage at loci enriched in simple repeats, which are known to challenge replication fork progression. Our findings illuminate a critical genetic buffering mechanism that provides an essential function for maintaining genome integrity.

molecular biology↗

bioRxiv2021

Guiding ATR and PARP inhibitor combinations with chemogenomic screens

Combinations of inhibitors of Ataxia Telangiectasia- and Rad3-related kinase (ATRi) and poly(ADP-ribose) polymerases (PARPi) synergistically kill tumor cells through modulation of complementary DNA repair pathways, but their tolerability is limited by hematological toxicities. To address this we performed a genome-wide CRISPR/Cas9 screen to identify genetic alterations that hypersensitize cells to a combination of the ATRi RP-3500 with PARPi, including deficiency in RNase H2, RAD51 paralog mutations or the Alternative Lengthening of Telomeres telomere maintenance mechanism. We show that RP-3500 and PARPi combinations kill cells carrying these genetic alterations at doses sub-therapeutic as single agents. We also demonstrate the mechanism of combination hypersensitivity in RNase H2-deficient cells, where we observe an irreversible replication catastrophe, allowing us to design a highly efficacious and tolerable in vivo dosing schedule. Altogether, we present a comprehensive dataset to inform development of ATRi and PARPi combinations and an experimental framework applicable to other drug combination strategies.

cancer biology↗