👤 Jerry Kelleher

GATA family transcription factors are somatically variable (SV) in esophageal adenocarcinomas (EAC) and inducible by simulated reflux. Our study examines the mechanisms whereby GATA family members (GATA4, GATA6, and the atypical TRPS-1) influence oncogenesis during the Barrett's esophagus (BE) metaplasia-dysplasia transition preceding EAC. RNAseq analyses of esophageal cell lines and lesion-derived adult stem cells (ASCs) in conjunction shRNA- or CRISPR-facilitated gene silencing, together with reanalysis of The Cancer Genome Atlas data, spatial transcriptomics, and organ-on-a-chip studies were used. Although a gastroesophageal reflux disease history positively correlated with GATA4/6 somatically variable and a columnar-associated gene signature (ANPEP/GATA4) in The Cancer Genome Atlas EAC cases, it negatively associated with a squamous lineage-linked signature (TP63/SOX15) containing TRPS1. In experimental data, opposing effects on regulators of squamous and columnar lineage identity were uncovered between TRPS1 and classical GATA factors (GATA4/6). Interrogation of this GATA "fulcrum" defined further genes (CGN, IL6R, and GPRC5B) targeted for TRPS1-mediated suppression or GATA4/6 activation. A novel spatial transcriptomic signature of BE-associated high-grade dysplasia (HGD) captured GATA fulcrum action, through GPRC5B expression. Functionally, GPRC5B was found to be low-pH-responsive, to increase proliferative and colony formation rates, and when overexpressed facilitate a hyperproliferative HGD-like transformation of BE-ASCs. Using an organ-on-a-chip platform, cellular overgrowth, reduced luminal villus structures, lower goblet cell numbers, and loss of intestine-associated marker gene expression (TFF3/MUC2) were observed following GPRC5B overexpression in BE-ASCs, mirroring HGD. This study identifies critical GATA factor-mediated processes underlying cellular phenotype in the BE-HGD-EAC transition and identifies GATA-inducible GPRC5B as a functional marker and possible driver of progression through HGD to EAC. Show less

Alzheimer's disease (AD) accounts for approximately 60% of dementia cases worldwide. Advanced age is the most significant risk factor for AD and approximately two-thirds of cases relate to women. While the previous meta-analysis suggests that estrogen receptor (ESR) genetic polymorphisms are closely associated with dementia, the implications of this observation on a molecular level are not entirely understood. Our study explores this intricate molecular puzzle through the use of a variety of bioinformatics tools. Initially, we attempted to elucidate mechanisms underlying breast cancer development by identifying the high-throughput dataset of Show less

Metabolic adaptations are triggered in the maternal organism to synthesize milk with an adequate concentration of long-chain polyunsaturated fatty acids (LC-PUFAs) required to the newborn. They may be a high uptake of dietary linoleic acid and its conversion to LC-PUFAs by desaturases of fatty acids (FADS) 1 and 2 in the mammary gland (MG). It is unknown if they also occur from onset of pregnancy. The aim of this study was to explore the participation of the MG as a mechanism involved in LC-PUFAs synthesis to support their demand during pregnancy and lactation in rats. The expression of desaturases in MG was significantly (P<0.05) higher (12.3-fold for FADS1 and 41.2-fold for FADS2) during the late pregnancy and throughout lactation (31.7-fold for FADS1 and 67.1-fold higher for FADS2) than in nonpregnant rats. SREBF-1c showed a similar pattern of increase during pregnancy but remained higher only during the early lactation (11.7-fold, P<0.005). Transcript of ELOVL6 and FASN increased throughout pregnancy and lactation, respectively. ELOVL5 mRNA increased in MG only during lactation (2.8 to 5.3-fold, P<0.005). Accordingly, a higher content of LC-PUFAs was found in lactating MG than in nonpregnant rats. Results suggest that MG participates from late pregnancy and throughout lactation by expressing desaturases and elongases as a mechanism involved in LC-PUFAs synthesis, probably by SREBF-1c. Because desaturases and ELOVL5 were expressed in cultured lactocytes and such expression was downregulated by linoleic and arachidonic acid, these cells may be a useful model for understanding the regulatory mechanisms for LC-PUFAs synthesis in MG. Show less

Langer-Giedion syndrome results from a microdeletion at 8q24.1 encompassing the EXT1 and the adjacent TRPS1 gene. We report on a boy with an oligo array-cgh characterized small microdeletion involving EXT1 alone but with some features of Langer-Giedion syndrome suggesting a functional disturbance of TRPS1. This boy, in addition to a mild Langer-Giedion like phenotype, also had some unusual features including prominent toe pads and fat pads on the soles of his feet similar to those described in Pierpont syndrome. Show less

Nogo receptor (NgR)-mediated control of axon growth relies on the central nervous system-specific type I transmembrane protein Lingo-1. Interactions between Lingo-1 and NgR, along with a complementary co-receptor, result in neurite and axonal collapse. In addition, the inhibitory role of Lingo-1 is particularly important in regulation of oligodendrocyte differentiation and myelination, suggesting that pharmacological modulation of Lingo-1 function could be a novel approach for nerve repair and remyelination therapies. Here we report on the crystal structure of the ligand-binding ectodomain of human Lingo-1 and show it has a bimodular, kinked structure composed of leucine-rich repeat (LRR) and immunoglobulin (Ig)-like modules. The structure, together with biophysical analysis of its solution properties, reveals that in the crystals and in solution Lingo-1 persistently associates with itself to form a stable tetramer and that it is its LRR-Ig-composite fold that drives such assembly. Specifically, in the crystal structure protomers of Lingo-1 associate in a ring-shaped tetramer, with each LRR domain filling an open cleft in an adjacent protomer. The tetramer buries a large surface area (9,200 A2) and may serve as an efficient scaffold to simultaneously bind and assemble the NgR complex components during activation on a membrane. Potential functional binding sites that can be identified on the ectodomain surface, including the site of self-recognition, suggest a model for protein assembly on the membrane. Show less