Biology subjects

Alpsoy, A.

Publications and source records attributed to Alpsoy, A..

4 recordsLinked to original sources

bioRxiv2024

Loss of Bicra/Gltscr1 leads to a defect in fetal liver macrophages responsible for erythrocyte maturation in mice.

Key pointsBicra/Gltscr1 homozygous knockout mice are perinatal lethal with aberrant liver resident macrophage gene expression and function. Dysfunctional macrophages result in accumulation of immature nucleated red blood cells in peripheral blood and liver of the knockout mice. GLTSCR1, a protein encoded by the Bicra gene, is a defining subunit of the SWI/SNF (also called mammalian BAF) chromatin remodeling subcomplex called GBAF/ncBAF. To determine the role of GLTSCR1 during mouse development, we generated a Bicra germline knockout mouse using CRISPR/Cas9. Mice with homozygous loss of Bicra were born at Mendelian ratios but were small, pale and died within 24 hours after birth. Histology indicated blood-related defects including defective erythroblastic islands and irregularly sized red blood cells. Gene expression profiling of fetal livers pinpointed a defect in liver resident macrophages involved in the last stage of erythrocyte maturation, resulting in accumulation of nucleated erythrocytes in Bicra-/- pups. Together, these results demonstrate that Bicra is critical for fetal liver macrophage function during development. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/618940v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@150ac36org.highwire.dtl.DTLVardef@15a4758org.highwire.dtl.DTLVardef@2176aorg.highwire.dtl.DTLVardef@14f5d49_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOVisual AbstractC_FLOATNO C_FIG

developmental biology↗

bioRxiv2024

MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer

The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. Here, we used paralog co-targeting CRISPR screens to identify the kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show exerts anti-tumor activity in vivo. Together, these findings reveal MARK2/3 as powerful co-dependencies of YAP/TAZ in human cancer; targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression.

cancer biology↗

bioRxiv2023

Marker-based CRISPR screening reveals a MED12-p63 interaction that activates basal identity in pancreatic ductal adenocarcinoma

The presence of basal lineage characteristics signifies hyper-aggressive human adenocarcinomas of the breast, bladder, and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC). This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor p63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements. Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to classical PDAC. Taken together, our comprehensive genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics.

cancer biology↗

bioRxiv2018

A chemoproteomic portrait of the oncometabolite fumarate

Hereditary cancer disorders often provide an important window into novel mechanisms supporting tumor growth and survival. Understanding these mechanisms and developing biomarkers to identify their presence thus represents a vital goal. Towards this goal, here we report a chemoproteomic map of the covalent targets of fumarate, an oncometabolite whose accumulation marks the genetic cancer predisposition syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). First, we validate the ability of known and novel chemoproteomic probes to report on fumarate reactivity in vitro. Next, we apply these probes in concert with LC-MS/MS to identify cysteine residues sensitive to either fumarate treatment or fumarate hydratase (FH) mutation in untransformed and human HLRCC cell models, respectively. Mining this data to understand the structural determinants of fumarate reactivity reveals an unexpected anti-correlation with nucleophilicity, and the discovery of a novel influence of pH on fumarate-cysteine interactions. Finally, we show that many fumarate-sensitive and FH-regulated cysteines are found in functional protein domains, and perform mechanistic studies of a fumarate-sensitive cysteine in SMARCC1 that lies at a key protein-protein interface in the SWI-SNF tumor suppressor complex. Our studies provide a powerful resource for understanding the influence of fumarate on reactive cysteine residues, and lay the foundation for future efforts to exploit this distinct aspect of oncometabolism for cancer diagnosis and therapy.

cancer biology↗