Gene Compass

[Sebastian Thorndike]

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The COMPASS protein family catalyzes histone H3 Lys 4 (H3K4) methylation and its members are essential for regulating gene expression. MLL2/COMPASS methylates H3K4 on many developmental genes and bivalent clusters. To understand MLL2-dependent transcriptional regulation, we performed a CRISPR-based screen with an MLL2-dependent gene as a reporter in mouse embryonic stem cells. We found that MLL2 functions in gene expression by protecting developmental genes from repression via repelling PRC2 and DNA methylation machineries. Accordingly, repression in the absence of MLL2 is relieved by inhibition of PRC2 and DNA methyltransferases. Furthermore, DNA demethylation on such loci leads to reactivation of MLL2-dependent genes not only by removing DNA methylation but also by opening up previously CpG methylated regions for PRC2 recruitment, diluting PRC2 at Polycomb-repressed genes. These findings reveal how the context and function of these three epigenetic modifiers of chromatin can orchestrate transcriptional decisions and demonstrate that prevention of active repression by the context of the enzyme and not H3K4 trimethylation underlies transcriptional regulation on MLL2/COMPASS targets.

We thank the Shilatifard laboratory members for helpful suggestions and discussions. K.A.H. and B.D.S. are supported by NIH K08HL128867. C.C.S. is supported, in part, by the NIH Predoctoral to Postdoctoral Transition Award F99CA234945. K.C. is supported, in part, by the NIH Pathway to Independence Award K99HD094906. A.P. is supported by the NIH Pathway to Independence Award K99CA234434. E.R.S. is supported by NIH R50CA211428. We thank N. J. Ethen for the graphical representation of the model (Fig. 8). Studies in the Shilatifard laboratory related to COMPASS are supported by the NCI Outstanding Investigator Award R35CA197569.

a, FACS analysis of mCherry-Magohb MLL2KO mESCs transformed with an empty vector or a MLL2 expressing vector. The experiment was repeated three times independently with similar results. b, Western blot for FLAG-MAGOHB expression in WT cells expressing a shRNA control (shNT) or a shRNA targeting MLL2 (shMLL2). The experiment was repeated two times independently with similar results. c, Western blot for CAS9, FLAG-MAGOHB and TUBULIN (loading control) protein levels in WT, Magohb KI WT cells (WT-MagohbKI) and Magohb KI MLL2KO cells (MLL2KO-MagohbKI). The experiment was repeated two times independently with similar results. d, Top panel: mCherry high cells were isolated via two successive rounds of FACS in MLL2KO mESCs. Bottom panel: mCherry low cells were isolated via two successive rounds of FACS in WT mESCs. The experiment was repeated three times independently with similar results. Uncropped gels are available as source data.

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Epigenetic regulation of gene expression in metazoans is central for establishing cellular diversity, and its deregulation can result in pathological conditions. Although transcription factors are essential for implementing gene expression programs, they do not function in isolation and require the recruitment of various chromatin-modifying and -remodeling machineries. A classic example of developmental chromatin regulation is the balanced activities of the Polycomb group (PcG) proteins within the PRC1 and PRC2 complexes, and the Trithorax group (TrxG) proteins within the COMPASS family, which are highly mutated in a large number of human diseases. In this review, we will discuss the latest findings regarding the properties of the PcG and COMPASS families and the insight they provide into the epigenetic control of transcription under physiological and pathological settings.

Our team includes physicians and nurses with advanced expertise in cancer genetics and genetic counseling. They have the experience to evaluate family history, provide knowledgeable guidance about cancer detection and prevention, and interpret the results of testing. Learn more about how genetic testing can help detect cancer earlier for people at a higher risk of developing cancer.

Lisa Clark, FNP, AOCNP, APNG

Lisa's experience with women coping with ovarian cancer inspired her interest in genetic research and cancer prevention. She has advanced certifications as a Family Nurse Practitioner (FNP), an Advanced Oncology Certified Nurse Practitioner (AOCNP), and an Advanced Practice Nurse in Genetics (APNG).

Becky Clark, MS, CGC

Becky completed her Master of Science degree in Genetic Counseling at the University of Michigan. She believes the most important aspect of genetic counseling is to provide patients with support and education so they can make informed decisions in their healthcare.

Scientists have been able to identify several specific inherited mutations that can lead to cancer. The Hereditary Breast and Ovarian Cancer (HBOC) syndrome caused by mutations in the BRCA1 and BRCA2 genes is probably the best known. Hereditary Non-Polyposis Colon Cancer (HNPCC), or Lynch syndrome, comprises colon cancer, ovarian cancer, and endometrial cancer. Other types of cancer caused by inherited gene mutations include kidney cancer, melanoma, brain tumors, prostate cancer, pancreatic cancer, and thyroid cancer.

Our knowledge of inherited gene mutations that can lead to cancer is growing rapidly, thanks to research and new panel-based genetic testing. Compass Oncology was an early adopter of this exciting technology which allows us to look at a large set of genes in a single test. As a result, we are redefining syndromes and discovering more connections between cancers. We know certain mutations can be responsible for multiple types of cancer. We have new risk models we can explore and in certain instances, knowing exactly what mutations are present can influence therapy.

Some individuals are born with genetic mutations that increase the risk of developing cancer during their lifetime. These mutations may be inherited from either a mother or a father. While simply having a genetic mutation does not mean you will definitely get cancer, it does increase your risk.

We are now in the era of personalized medicine and genetic counseling. Your genes can predict your risk of cancer, and certain genetic tests may help your doctors provide better treatment options. If you have cancer in your family, you may be at higher risk. You can talk to one of our genetic counselors to see if genetic testing for cancer would be right for you and your family.

Consider scheduling a personalized genetic risk evaluation with Compass Oncology genetic counselor if you or any family member on either side of your family meet any of the following criteria of the syndromes outlined below.

Since the technology for testing has progressed over the years, our genetic counselors also encourage anyone that meets any of the criteria outlined above but received a negative genetic test prior to 2013, to be retested. New genes associated with cancer risks and syndromes have been identified and are now included in updated panel-based testing.

Most insurance will cover genetic testing for patients who meet basic criteria. Our counselors are available to help you determine if you meet these criteria. To schedule your appointment, please call 971.708.7600.

A new Northwestern Medicine study published on the cover of Nature Genetics has reported that a transcriptional regulator called MLL2/COMPASS actually repels negative regulation, rather than being a positive regulator, as previously thought.

This distinction sheds new light on the impact of the COMPASS family of transcriptional regulators, according to Ali Shilatifard, PhD, the Robert Francis Furchgott Professor, chair of Biochemistry and Molecular Genetics and senior author of the study.

However, the functions of the constituent subunits in the complex that make up the COMPASS protein are still unclear, according to Shilatifard. In the current study, Delphine Douillet, PhD, first author of the study and former postdoctoral fellow in the Shilatifard laboratory, identified a gene target that required both MLL2 and H3K4 methylation for its expression.

Other co-authors include Shilatifard laboratory members Christie Sze, graduate student; Caila Ryan, research technician; Andrea Piunti, PhD, postdoctoral fellow; Avani Shah, research technician; Emily Rendleman, laboratory manager; Didi Zha, research technician; Zibo Zhao, PhD, postdoctoral fellow; former Shilatifard laboratory members Michael Ugarenko, research staff; Stacy Marshall, research staff; and Kathryn Helmin, manager in the Singer laboratory,

As the use of genetic testing becomes more routine in the workup for IEIs, it is important for providers to know the types of tests available and the technical components that maximize diagnoses. In this webinar, Clinical Genomic Liaison Torry Howell, MS, CGC will review the use of genetic testing in IEIs and advise on how to maximize quality and patient care when ordering genetic testing.

Histone H3 lysine-4 (H3K4) methylation is associated with transcribed genes in eukaryotes. In Drosophila and mammals, both di- and tri-methylation of H3K4 are associated with gene activation. In contrast to animals, in Arabidopsis H3K4 trimethylation, but not mono- or di-methylation of H3K4, has been implicated in transcriptional activation. H3K4 methylation is catalyzed by the H3K4 methyltransferase complexes known as COMPASS or COMPASS-like in yeast and mammals. Here, we report that Arabidopsis homologs of the COMPASS and COMPASS-like complex core components known as Ash2, RbBP5, and WDR5 in humans form a nuclear subcomplex during vegetative and reproductive development, which can associate with multiple putative H3K4 methyltransferases. Loss of function of ARABIDOPSIS Ash2 RELATIVE (ASH2R) causes a great decrease in genome-wide H3K4 trimethylation, but not in di- or mono-methylation. Knockdown of ASH2R or the RbBP5 homolog suppresses the expression of a crucial Arabidopsis floral repressor, FLOWERING LOCUS C (FLC), and FLC homologs resulting in accelerated floral transition. ASH2R binds to the chromatin of FLC and FLC homologs in vivo and is required for H3K4 trimethylation, but not for H3K4 dimethylation in these loci; overexpression of ASH2R causes elevated H3K4 trimethylation, but not H3K4 dimethylation, in its target genes FLC and FLC homologs, resulting in activation of these gene expression and consequent late flowering. These results strongly suggest that H3K4 trimethylation in FLC and its homologs can activate their expression, providing concrete evidence that H3K4 trimethylation accumulation can activate eukaryotic gene expression. Furthermore, our findings suggest that there are multiple COMPASS-like complexes in Arabidopsis and that these complexes deposit trimethyl but not di- or mono-methyl H3K4 in target genes to promote their expression, providing a molecular explanation for the observed coupling of H3K4 trimethylation (but not H3K4 dimethylation) with active gene expression in Arabidopsis.

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