Distinct Classes of Lamin-Associated Domains are Defined by Differential Patterns of Repressive Histone Methylation.

A large fraction of the genome interacts with the nuclear periphery through lamina-associated domains (LADs), repressive regions which play an important role in genome organization and gene regulation across development. Despite much work, LAD structure and regulation are not fully understood, and a mounting number of studies have identified numerous genetic and epigenetic differences within LADs, demonstrating they are not a uniform group. Here we profile Lamin B1, HP1β, H3K9me3, H3K9me2, H3K27me3, H3K14ac, H3K27ac, and H3K9ac in MEF cell lines derived from the same mouse colony and cluster LADs based on the abundance and distribution of these features across LADs.

Single Nuclei Sequencing Reveals Intratumoral Cellular Heterogeneity and Replication Stress in Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis and limited treatment options. Bulk genomic characterization of ACC has not yielded obvious therapeutic or immunotherapeutic targets, yet novel therapies are needed. We hypothesized that elucidating the intratumoral cellular heterogeneity by single nuclei RNA sequencing analyses would yield insights into potential therapeutic vulnerabilities of this disease.

Bioengineered in vitro three-dimensional tumor models in endocrine cancers.

Abstract: Endocrine tumors are a heterogeneous cluster of malignancies that originate from cells that can secrete hormones. Examples include, but are not limited to, thyroid cancer, adrenocortical carcinoma, and neuroendocrine tumors. Many endocrine tumors are relatively slow to proliferate, and as such, they often do not respond well to common antiproliferative chemotherapies.

A 3D adrenocortical carcinoma tumor platform for preclinical modeling of drug response and matrix metalloproteinase activity.

Adrenocortical carcinoma (ACC) has a poor prognosis, and no new drugs have been identified in decades. The absence of drug development can partly be attributed to a lack of preclinical models. Both animal models and 2D cell cultures of ACC fail to accurately mimic the disease, as animal physiology is inherently different than humans, and 2D cultures fail to represent the crucial 3D architecture.

A 3D adrenocortical carcinoma tumor platform for preclinical modeling of drug response and matrix metalloproteinase activity.

Adrenocortical carcinoma (ACC) has a poor prognosis, and no new drugs have been identified in decades. The absence of drug development can partly be attributed to a lack of preclinical models. Both animal models and 2D cell cultures of ACC fail to accurately mimic the disease, as animal physiology is inherently different than humans, and 2D cultures fail to represent the crucial 3D architecture.

Epigenetic regulation of nuclear lamina-associated heterochromatin by HAT1 and the acetylation of newly synthesized histones.

A central component of the epigenome is the pattern of histone post-translational modifications that play a critical role in the formation of specific chromatin states. Following DNA replication, nascent chromatin is a 1:1 mixture of parental and newly synthesized histones and the transfer of modification patterns from parental histones to new histones is a fundamental step in epigenetic inheritance. Here we report that loss of HAT1, which acetylates lysines 5 and 12 of newly synthesized histone H4 during replication-coupled chromatin assembly, results in the loss of accessibility of large domains of heterochromatin, termed HAT1-dependent Accessibility Domains (HADs).

Histone acetyltransferase 1 is required for DNA replication fork function and stability.

The replisome is a protein complex on the DNA replication fork and functions in a dynamic environment at the intersection of parental and nascent chromatin. Parental nucleosomes are disrupted in front of the replication fork. The daughter DNA duplexes are packaged with an equal amount of parental and newly synthesized histones in the wake of the replication fork through the activity of the replication-coupled chromatin assembly pathway.

Early-onset aging and mitochondrial defects associated with loss of histone acetyltransferase 1 (Hat1).

Histone acetyltransferase 1 (Hat1) is responsible for the acetylation of newly synthesized histone H4 on lysines 5 and 12 during the process of chromatin assembly. To understand the broader biological role of Hat1, we have generated a conditional mouse knockout model of this enzyme. We previously reported that Hat1 is required for viability and important for mammalian development and genome stability.