Drivers Chromation

As part of the new class of Pew-Stewart Scholars, geneticist Chao Lu, PhD, is taking a close look at chromatin’s role in cancer and other human diseases. Work in the Lu lab has revealed that cancer-associated mutations in chromatin modulators are drivers of tumor development. A key goal is to determine which of these chromatin mutations are druggable, and down the road, to add innovative chromatin-based therapies to current oncology practice.

This new data suggests that Alzheimer’s disease involves a reconfiguration of the epigenomic landscape, with the marks H3K27ac and H3K9ac affecting disease pathways by disrupting the transcription- and chromatin-gene feedback loops. Genes encoding proteins that regulate chromatin structure and DNA modifications i.e., chromatin regulatory factors (CRF) and genes encoding histone proteins harbor recurrent mutations in most human cancers. These mutations lead to modifications in tumor chromatin and DNA structure and an altered epigenetic state that contribute to tumorigenesis. Mutated CRFs have now been identified in most. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. (Schwartzentruber, J. Research article; Open Access; Published: 06 November 2018 A pan-cancer analysis of driver gene mutations, DNA methylation and gene expressions reveals that chromatin remodeling is a major mechanism inducing global changes in cancer epigenomes. The contact frequencies and the subsequent chromatin 3D modeling are based on these Hi-C (genome-wise chromatin conformation capturing technology) data. Mapping peptides to human genome To map the peptides to human genome (hg19), we wrote a pipeline to query the BLAST 24 web server and map the gene names to chromosomes and starting positions.

Dr. Lu, assistant professor of genetics and development at Columbia University Irving Medical Center and a member of the Herbert Irving Comprehensive Cancer Center (HICCC) at NewYork-Presbyterian/Columbia, is one of just seven new Pew-Stewart Scholars for Cancer Research announced June 14 by the Pew Charitable Trust. The prestigious four-year grant, funded by the Alexander and Margaret Stewart Trust and administered by Pew, supports promising early career scientists whose research will accelerate discovery and advance progress to a cure for cancer. In 2019, the seven scientists were selected out of a pool of 62 nationwide, and to date, there are 32 Pew-Stewart Scholars working to solve cancer.

Dr. Lu is bringing his interdisciplinary expertise in cancer biology and chromatin regulation to examine the fundamentals of tumor development and identify new potentially druggable targets, looking beyond single genetic mutations that contribute to cancer.

In its textbook role, chromatin’s primary function is to package long, complex DNA molecules in a precise way that protects DNA’s structure and plays a crucial role in many important biological processes, including cell division and gene expression regulation. As Dr. Lu puts it, “It has been known to be a ‘boring’ mechanism to study.” But in the past 20 years with the advent of next-generation sequencing technology, scientists have been able to systematically sequence the tumor genome, and in doing so, have revealed much more that how aberrant chromatin organization can potentially drive tumorigenesis.

“When scientists first started to sequence different cancer types, obviously they got some of the usual suspects, which are the genes we know that cause cancer but they also got a lot of surprises,” says Dr. Lu. “Among the genes we didn’t know that were involved in the tumorigenic process are chromatin-associated proteins which are involved in genome regulation. Chromatin’s function in packaging DNA itself contains a lot of regulation, and we now appreciate that if that process is abnormal, all kinds of disease can happen, not just cancer.”

ChromationDrivers chromatin vs

Dr. Lu and his lab are trying to understand how chromatin regulators promote tumorigenesis and to consider new strategies for therapeutically targeting tumors with chromatin mutation. “This is not your conventional, textbook oncogenes and tumor suppressors. We’ll need a new way to target them,” notes Dr. Lu.

Through a combination of high-throughput genetic approaches and biochemistry, Lu and his group are aiming to discover how the mutation in chromatin regulators change the genome regulation landscape, which in turn are effecting different cancer hallmarks.

Dr. Lu joined Columbia University in the spring of 2018 from Rockefeller University, where he was a post-doctoral fellow in Dr. C. David Allis’ Laboratory of Chromatin Biology and Epigenetics. Dr. Lu wanted to pair his previous training in cancer biology to a broad area of basic research, which is what attracted him to chromatin, specifically chromatin malfunction as a new mechanism responsible for cancer progression.

“In addition to its link to cancer, I was and am intrigued by the chromatin itself and by its very complex interaction to ensure our genes are properly regulated,” says Dr. Lu. “I continue to be amazed by the sophisticated process in which our cells package our genome and access them in a highly regulated manner.”

Drivers chromatin definition

Dr. Lu joins an innovative class of Pew-Stewart scholars whose research aims to better understand the origins, diagnosis, and treatment of cancer. Pew scholars gather annually in March for Pew's annual meeting in the biomedical sciences, where they are recognized and network with peers in the field. In 2018, Dr. Lu received the AACR Gertrude B. Elion Cancer Research Award and in 2017, the Damon Runyon-Dale F. Frey Award for Breakthrough Scientists and Blavatnik Regional Award for Young Scientists.

Drivers Chromatin Definition

Drivers chromatin model

Drivers Chromatin Model

-Melanie A. Farmer

Drivers Chromatin Vs


Drivers Chromatin Test

  • Linker histone H1 proteins bind to nucleosomes and facilitate chromatin compaction1, although their biological functions are poorly understood. Mutations in the genes that encode H1 isoforms B-E (H1B, H1C, H1D and H1E; also known as H1-5, H1-2, H1-3 and H1-4, respectively) are highly recurrent in B cell lymphomas, but the pathogenic relevance of these mutations to cancer and the mechanisms that are involved are unknown. Here we show that lymphoma-associated H1 alleles are genetic driver mutations in lymphomas. Disruption of H1 function results in a profound architectural remodelling of the genome, which is characterized by large-scale yet focal shifts of chromatin from a compacted to a relaxed state. This decompaction drives distinct changes in epigenetic states, primarily owing to a gain of histone H3 dimethylation at lysine 36 (H3K36me2) and/or loss of repressive H3 trimethylation at lysine 27 (H3K27me3). These changes unlock the expression of stem cell genes that are normally silenced during early development. In mice, loss of H1c and H1e (also known as H1f2 and H1f4, respectively) conferred germinal centre B cells with enhanced fitness and self-renewal properties, ultimately leading to aggressive lymphomas with an increased repopulating potential. Collectively, our data indicate that H1 proteins are normally required to sequester early developmental genes into architecturally inaccessible genomic compartments. We also establish H1 as a bona fide tumour suppressor and show that mutations in H1 drive malignant transformation primarily through three-dimensional genome reorganization, which leads to epigenetic reprogramming and derepression of developmentally silenced genes.