Evaluation of Hsp90 and mTOR inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer.

Inactivating mutations in either TSC1 or TSC2 cause Tuberous Sclerosis Complex, an autosomal dominant disorder, characterized by multi-system tumor and hamartoma development. Mutation and loss of function of TSC1 and/or TSC2 also occur in a variety of sporadic cancers, and rapamycin and related drugs show highly variable treatment benefit in patients with such cancers. The TSC1 and TSC2 proteins function in a complex that inhibits mTORC1, a key regulator of cell growth, which acts to enhance anabolic biosynthetic pathways.

A synthetic biology approach to probing nucleosome symmetry.

The repeating subunit of chromatin, the nucleosome, includes two copies of each of the four core histones, and several recent studies have reported that asymmetrically-modified nucleosomes occur at regulatory elements in vivo. To probe the mechanisms by which histone modifications are read out, we designed an obligate pair of H3 heterodimers, termed H3X and H3Y, which we extensively validated genetically and biochemically. Comparing the effects of asymmetric histone tail point mutants with those of symmetric double mutants revealed that a single methylated H3K36 per nucleosome was sufficient to silence cryptic transcription in vivo.

A small molecule inhibitor of fungal histone acetyltransferase Rtt109.

The histone acetyltransferase Rtt109 is the sole enzyme responsible for acetylation of histone H3 lysine 56 (H3K56) in fungal organisms. Loss of Rtt109 renders fungal cells extremely sensitive to genotoxic agents, and prevents pathogenesis in several clinically important species. Here, via a high throughput chemical screen of >300,000 compounds, we discovered a chemical inhibitor of Rtt109 that does not inhibit other acetyltransferase enzymes.

Angiomyolipoma have common mutations in TSC2 but no other common genetic events.

Renal angiomyolipoma are part of the PEComa family of neoplasms, and occur both in association with Tuberous Sclerosis Complex (TSC) and independent of that disorder. Previous studies on the molecular genetic alterations that occur in angiomyolipoma are very limited. We evaluated 9 angiomyolipoma for which frozen tissue was available from a consecutive surgical series.

Characterization of the human SLC22A18 gene promoter and its regulation by the transcription factor Sp1.

SLC22A18, a poly-specific organic cation transporter, is paternally imprinted in humans and mice. It shows loss-of-heterozygosity in childhood and adult tumors, and gain-of-imprinting in hepatocarcinomas and breast cancers. Despite the importance of this gene, its transcriptional regulation has not been studied, and the promoter has not yet been characterized.

Promoter characterization and regulation of expression of an imprinted gene SLC22A18AS.

The SLC22A18/SLC22A18AS genes are a sense-antisense pair located at human chromosome segment 11p15.5. These genes are paternally imprinted: paternal alleles are silenced and maternal alleles are expressed.

Role of CYP1B1, MYOC, OPTN, and OPTC genes in adult-onset primary open-angle glaucoma: predominance of CYP1B1 mutations in Indian patients.

Purpose: Mutations in the CYP1B1, MYOC, OPTN, and WDR36 genes result in glaucoma. Given its expression in the optic nerve, it is likely a mutation in the OPTC gene is also involved in initiating glaucoma. This study was designed to evaluate the involvement of the CYP1B1, MYOC, OPTN, and OPTC genes in the etiology of adult-onset primary open-angle glaucoma (POAG) found in 251 Indian patients.

Paternal imprinting of the SLC22A1LS gene located in the human chromosome segment 11p15.5.

Background: Genomic imprinting is an epigenetic chromosomal modification in the gametes or zygotes that results in a non-random monoallelic expression of specific autosomal genes depending upon their parent of origin. Approximately 44 human genes have been reported to be imprinted. A majority of them are clustered, including some on chromosome segment 11p15.