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Chromatin Rebuilding, Hemophilia Oral Treatment, Linking CVD and CKD, New Algorithm Detects Genetic Variants

Published on December 13, 2019 in Cornerstone Blog · Last updated 5 months 3 weeks ago


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In the NewsIn the News: Discoveries in cell structure and genetics

Before In the News takes a break to enjoy the holidays, join our researchers celebrating breakthroughs in understanding cell mitosis and a new research collaboration to develop an oral treatment for hemophilia. In addition, an innovative pilot study is underway to define the link between cardiovascular disease and pediatric chronic kidney disease, and a newly developed algorithm improves diagnostic rates for rare genetic diseases. 

Scientists Detail How Chromosomes Reorganize After Cell Division

Researchers from Children’s Hospital of Philadelphia and the University of Pennsylvania  discovered how a cell nucleus and its chromosomal material reorganizes itself after cell division. 

“It’s long been an open question in biology of exactly how the genome is organized in the nucleus,” said study leader Gerd A. Blobel, MD, PhD, Frank E. Weise III Endowed Chair in Pediatric Hematology at CHOP, and a professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “All the DNA bases in the genome of one cell, if uncoiled into a straight line, would extend for two meters. Yet this material is confined into a tiny space within each cell nucleus, and requires highly organized packaging.”

In their findings published in Nature, Dr. Blobel and colleagues describe the formation of structures in chromatin; the appearance and expansion of transcriptionally active and silenced compartments; the creation of contact between regulatory regions of the genome; and changes in CTCF and cohesion, architectural proteins that help sculpt the genome. 

Working with blood-forming cells from a well-established mouse model, the researchers used sophisticated high-throughput chromosome conformation capture to detect and map interactions across three-dimensional space between specific sites in chromosomal DNA. These maps also allowed the scientists to measure such interactions at different time points in the cell cycle, detecting roughly 2 billion interactions during and following mitosis.

In addition to delineating a crucial process in cell biology, the research delved into what Dr. Blobel called “the complicated interplay between chromatin architecture and gene transcription.” Gene mutations that disrupt normal genome architecture or transcription can play a key role in disease, so a better understanding of chromatin architecture has the potential for clinical importance in diseases where defects of cohesion can cause subtypes of multisystem genetic disorders, such as Cornelia de Lange syndrome.

Find out more in this CHOP press release.

CHOP and Bayer Collaborate on Research for Oral Treatment of Hemophilia

CHOP and Bayer announced a three-year collaboration agreement for the discovery and development of small molecules to develop a first-in-class oral non-replacement therapy for the treatment of hemophilia A and B. 

Hemophilia is a genetic bleeding disorder in which one of the clotting proteins needed to form blood clots in the body is missing or defective. More than 400,000 individuals worldwide live with hemophilia, for which the main treatment is a replacement therapy that must be injected multiple times a week to help replace the clotting factor the patient needs. The CHOP-Bayer collaboration will investigate an oral small molecule treatment for hemophilia with the potential to relieve patients from the necessity of frequent injections.

Learn more about novel therapies for hemophilia.

Study Seeks Obesity-Cardiovascular Disease Link in Pediatric Chronic Kidney Disease

Amy Kogon, MD, MPH, attending nephrologist and junior investigator at CHOP, is leading a pilot study using the Clinical Phenotyping Core of the recently established the Pediatric Center of Excellence in Nephrology (PCEN) to compare the energy balance, body composition, eating behaviors, and cardiovascular disease (CVD) markers of children with chronic kidney disease (CKD) to controls. Cardiovascular disease is one of the leading causes of death in children with CKD. 

Dr. Kogon’s central hypothesis is that pediatric CKD alters body composition so as to affect cardiovascular intermediate end points, such as heart structure and function, high blood pressure, and increase cardiovascular risk. This cross-sectional study of 53 children with CKD stage III to stage V and a comparable group of 53 unaffected children will assess alterations in energy balance, body composition, and eating behavior, and how these alterations associate with CVD markers. 

The study is remarkable for a variety of reasons, including its innovative use of dual-energy X-ray absorptiometry to measure body composition for the evaluation of CVD risk factors in pediatric CKD. It is the first study to measure key components of energy balance simultaneously with direct comparison to controls. It will directly measure body composition in relation to CVD markers, and it will use gold standard measures to improve upon previously collected data regarding nutritional intake and physical activity.

An additional distinction of Dr. Kogon’s study is its combination of precise physiology measures with behavioral measures (e.g., physical activity, dietary intake, eating behavior) in a population of children with CKD with the aim of providing new data to identify the most important risk factors for the development of obesity and CVD risk. Ultimately, the findings will be used to improve the duration and quality of life of children with CKD.

Learn more in the CHOP news release.

New Algorithm Better Detects Disease-Causing Genetic Variants

CHOP scientists developed an open-source algorithm that can detect disease-causing structural variants in the genome with high sensitivity. The new tool, LinkedSV, applies the algorithm to fragments of barcoded genomic material, allowing the identification of changes in the genome that previously evaded detection.

Kai Wang, PhD, a genomics researcher at the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at CHOP and associate professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania, developed the algorithm in collaboration with a team of scientists from CHOP’s Center for Applied Genomics, as well as the University of Pennsylvania and the Medical University Innsbruck in Austria. The new method appeared in Nature Communications.

“We are suggesting that the method can help improve the diagnostic rate for undiagnosed diseases,” Dr. Wang said, noting the algorithm is already being used at CHOP to reanalyze patients whose diagnoses may have been missed previously using other sequencing techniques. “We think this is a future direction that should be pursued.”

Current genome sequencing methods involve using short-reads, fragments of genomic material that are scanned for genetic anomalies and are, on average, 100 to 150 DNA base pairs long. Many disease-causing structural changes within the genome are much longer and thus difficult to detect using short-read sequencing technologies. As a result, traditional exome sequencing methods miss approximately 50 to 70 percent of potential diagnoses for rare undiagnosed diseases.

The LinkedSV method uses linked-read technology, fragmenting the genome into pieces 1,000 times longer than traditional sequencing methods. The longer snippets of genomic material were dispersed into droplet partitions, and each droplet was given a barcode. DNA sequences in the droplets from the same larger fragment received the same barcode, allowing the scientists to group together sequences that reside in proximity within the genome, resulting in much longer genomic sequences. This enabled the scientists to discover deletions, duplications, translocations, and inversions within the genome that traditional sequencing methods had missed.

In addition to its potential clinical use, the method is compatible with current sequencing procedures, requiring only the addition of the barcoding step through a microfluidic system.

“By adding a small extra cost, you may be able to analyze sequence data that is much more informative and can capture previously unseen structural changes in the human genome,” Dr. Wang said.


Catch up on our headlines from our Nov. 29 In the News:

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  • New Screening Approach for Retinopathy of Prematurity
  • Study Assessing Prenatal Stress Reveals Surprising Outcomes
  • Celebrate Our Scientific Achievements With the 2019 Annual Report

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