Research

KSOM faculty authors: Peggy Farnham (BMM), Suhn Rhie (BMM)
Publication: Nature. 2020; 583:699-710. doi: 10.1038/s41586-020-2493-4.
Link to the manuscript: https://www.nature.com/articles/s41586-020-2493-4

Many human diseases are caused by changes in the abundance or activity of proteins and RNAs encoded by segments of our DNA genome called genes. A challenge for medical sciences has been mapping the functional elements that provide specific instructions for expression of the genes in our different cell types. The Encyclopedia of DNA Elements (ENCODE) project was established to create a catalogue of these functional elements and to outline their roles in regulating gene expression in normal and diseased tissues. This international team of experts focused on understanding the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. They developed a registry of 926,535 human candidate cis-regulatory elements by integrating numerous datatypes associated with gene regulation, providing an incredible resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes. This online registry marks a true milestone, organizing an enormous amount of genomic information into a searchable encyclopedia of DNA elements, which is accessible at https://screen.encodeproject.org.

KSOM faculty authors: Suhn Rhie (BMM), Peggy Farnham (BMM), Ite Laird, Crystal Marconett, Zea Borok, Beiyun Zhou
Publication: PLoS Genet. 2020;16:e1009023. doi: 10.1371/journal.pgen.1009023.
Link to the manuscript: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009023

Lung cancer is the second most commonly diagnosed form of cancer and the leading cause of cancer-related death in both men and women. Although genetic alterations have been identified as drivers in subsets of lung adenocarcinoma, approximately a quarter of lung adenocarcinoma cases do not possess known mutations, fusions, and copy number variations, suggesting that epigenetic changes likely contribute to lung adenocarcinoma. The investigators developed a bioinformatics approach called TENET 2.0 to identify key transcriptional regulators linked to lung adenocarcinoma, as compared to normal lung. They found that high expression of the transcriptional regulators CENPA, MYBL2, and FOXM1 were linked to many cancer-specific regulatory elements of oncogenes, and high expression of these regulators was observed in a subgroup of lung adenocarcinomas showing poor patient survival. Their findings suggest that abnormal expression of these key transcriptional regulators drives epigenetic deregulation in lung adenocarcinoma, promoting future development of novel biomarkers and therapeutic targets. Importantly, TENET 2.0 represents an important contribution to the cancer research community as it can be used to investigate molecular mechanisms underlying any cancer type for which gene expression and epigenetic data are available; the program is publicly accessible (http://github.com/suhnrhie/TENET_2.0).

KSOM faculty authors: Amy Lee (BMM), Keigo Machida, Parkash Gill
Publication: Journal of Biological Chemistry, 2021, in press
Link to the manuscript: Coming soon

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 global pandemic, utilizes the host receptor angiotensin-converting enzyme 2 (ACE2) for viral entry. However, other host factors might also play important roles in SARS-CoV-2 infection, potentially providing new directions for antiviral treatments. GRP78 is a broadly expressed stress-inducible chaperone important for entry and infectivity for many viruses. Recent molecular docking analyses revealed a putative interaction site between GRP78 and the receptor binding domain of the SARS-CoV-2 Spike protein (SARS-2-S). Using biochemical and imaging approaches, the investigators established that GRP78 can form a complex with SARS-2-S and ACE2. The investigators showed that loss of GRP78 can markedly reduce cell surface ACE2 expression and activate the unfolded protein response, which is associated with viral infection. Treatment of cultured lung epithelial cells with a humanized monoclonal antibody against GRP78, which was selected on the basis of its safe clinical profile in preclinical models, depleted cell surface GRP78 and reduced cell surface ACE2 expression, SARS-2-S-driven viral entry, and SARS-CoV-2 infection. This study suggests that GRP78 is an important host auxiliary factor for SARS-CoV-2 entry and infection and a potential target in combination therapies to combat this novel pathogen; these studies may also provide new therapeutic options to target other viruses that utilize GRP78.

KSOM faculty authors: Amy Lee (BMM), Louis Dubeau, Beiyun Zhou, Zea Borok, Ite Offringa
Publication: Oncogene (2021).
Link to the manuscript: https://www.nature.com/articles/s41388-021-01791-9

Lung cancer is the leading cause of cancer mortality worldwide and KRAS is the most commonly mutated gene in lung adenocarcinoma (LUAD). The 78-kDa glucose-regulated protein GRP78 is a key endoplasmic reticulum chaperone protein and a major pro-survival effector of the unfolded protein response. Compared to normal lung, GRP78 expression is generally elevated in human lung cancers, including tumors bearing a KRASG12D mutation. To test the requirement of GRP78 in human lung oncogenesis, the investigators generated mouse models that allowed simultaneous activation of the KrasG12D mutation and knockout of the Grp78 gene. They report that GRP78 haploinsufficiency is sufficient to suppress KrasG12D-mediated lung tumor progression and can prolong survival. Furthermore, GRP78 knockdown in the human lung cancer cell line A427 (KrasG12D/+) leads to activation of the unfolded protein response and apoptotic markers and loss of cell viability. Their studies provide evidence that targeting GRP78 represents a novel therapeutic approach to suppress mutant KRAS -mediated lung tumorigenesis.

KSOM faculty authors: Oliver Bell (BMM) and Suhn Rhie (BMM)
Publication: Science Advances 01 Apr 2020. doi: 10.1126/sciadv.aax5692
Link to the manuscript: https://advances.sciencemag.org/content/6/14/eaax5692

Epigenetic mechanisms that stabilize cellular identity are critical for integrity of tissues and organs, and their alterations may result in various disorders such as cancer. The epigenetic regulators Polycomb repressive complex 1 (PRC1) and PRC2 are required to maintain cell fate during embryonic development. PRC1 and PRC2 catalyze distinct histone modifications, establishing repressive chromatin at shared targets. How PRC1, which consists of canonical PRC1 (cPRC1) and variant PRC1 (vPRC1) complexes, and PRC2 cooperate to silence genes and support mouse embryonic stem cell (mESC) self-renewal is unclear. Using combinatorial genetic perturbations, the investigators show that independent pathways of cPRC1 and vPRC1 are responsible for maintenance of H2A monoubiquitylation and silencing of shared target genes. Individual loss of PRC2-dependent cPRC1 or PRC2-independent vPRC1 disrupts only one pathway and does not impair mESC self-renewal capacity. However, loss of both pathways leads to mESC differentiation and activation of a subset of lineage-specific genes. Thus, together PRC1 and PRC2 act redundantly to maintain the repression of important developmental genes, providing robust control to safeguard stem cell identity to facilitate embryonic development.

KSOM faculty authors: Oliver Bell (BMM) Heinz Lenz, Shannon Mumenthaler, Yong-mi Kim
Publication: Biorxiv 02.2021
Link to the manuscript: https://www.biorxiv.org/content/10.1101/2021.02.23.432388v1

Specific targeting of epigenetic modifications to silence key developmental genes is controlled by chromobox (CBX) proteins (CBX2, 4, 6, 7 and 8). CBX protein misregulation is frequently associated with human disease including cancer, making them an attractive therapeutic target for drug development. The investigators discovered UNC7040, a potent, cellularly active chemical probe against CBX8. They showed that treatment with UNC7040 leads to efficient eviction of epigenetic regulators, loss of silencing, and reduced proliferation across different cancer cell lines. Their discovery and characterization of UNC7040 not only revealed the most cellularly potent CBX8-specific chemical probe to date, but also provides an impactful tool for future mechanistic studies and advances translation of epigenetic inhibitors into the clinic.