Breaking News
August 16, 2018 - Does medical school take too long?
August 16, 2018 - Brown University researchers reveal key physical properties of ‘giant’ cancer cells
August 16, 2018 - Regular resistance training improves exercise motivation
August 16, 2018 - Feds urge states to encourage cheaper plans off the exchanges
August 16, 2018 - Seven activities that prevent you from getting quality sleep during summer
August 16, 2018 - Five ways to tell if your baby is getting enough milk from breastfeeding
August 16, 2018 - From Pigs to Peacocks, What’s Up With Those ‘Emotional-Support Animals’?
August 16, 2018 - Breast cancers enlist the help of normal cells to help them spread and survive
August 16, 2018 - Engaging with “high-need” patients outside the clinic
August 16, 2018 - Research illuminates how online forum may offer suicide prevention support for males
August 16, 2018 - Researchers identify way to grow immune cells at large scale for preventing cancer reoccurrence
August 15, 2018 - Keck Medicine of USC’s hospitals ranked among nation’s best for the 10th consecutive year
August 15, 2018 - Researchers compare existing approaches for automating diagnostic procedures of skin lesions
August 15, 2018 - Autism risk determined by health of mom’s gut, research reveals
August 15, 2018 - WELL for Life challenges you to explore the great outdoors
August 15, 2018 - ‘Zombie’ gene protects elephants from cancer, study finds
August 15, 2018 - Ebola outbreak in Congo spreads to active combat zone
August 15, 2018 - Study highlights pollution exposure of babies in prams
August 15, 2018 - Study provides insight into link between sleep apnea and lipid metabolism
August 15, 2018 - New study focuses on promise of gene therapy for Amish nemaline myopathy
August 15, 2018 - Researchers discover new approach to alleviate chronic itch
August 15, 2018 - Uncovering the Mysteries of MS: Medical Imaging Helps NIH Researchers Understand the Tricky Disease
August 15, 2018 - Autistic people at greater risk of becoming homeless – new research
August 15, 2018 - New imaging technique can spot tuberculosis infection in an hour
August 15, 2018 - Scientists study effects of eating breakfast versus fasting overnight before exercise
August 15, 2018 - Talking with children about suicide could save lives
August 15, 2018 - Grip strength of children predicts future cardiometabolic health
August 15, 2018 - Innovative oncofertility program launched by RMA of New York and Mount Sinai Health System
August 15, 2018 - Study shows efficacy, safety of AAV5-based gene therapy to treat sheep model of achromatopsia
August 15, 2018 - Simple score helps predict which hospitalized heart attack patients are at high risk of readmissions
August 15, 2018 - New discoveries show how protein droplets do more than keep cells’ interiors tidy
August 15, 2018 - Study shows impact of optimizing airport flight patterns on human health
August 15, 2018 - Life experiences of feeling unwanted or unplanned associated with attachment insecurity
August 15, 2018 - ACS Briefing Discusses Use of Lessons From Combat Care
August 15, 2018 - Study identifies distinct origin of ADHD in children with history of brain injury
August 15, 2018 - IgG3 antibody stops B cells from fighting pathogens in HIV patients
August 15, 2018 - Scientists discover key vulnerability of mixed lineage leukemia
August 15, 2018 - College students may experience pressures from secondary exposure to opioid abuse
August 15, 2018 - Powerful new microscope reveals inner workings of human cells with unprecedented clarity
August 15, 2018 - Married people who fight nastily more likely to suffer from leaky guts, study suggests
August 15, 2018 - Working Out After Baby – Drugs.com MedNews
August 15, 2018 - Rheumatoid Factor (RF) Test: MedlinePlus Lab Test Information
August 15, 2018 - ADHD linked to an increased risk of injury in children, study finds
August 15, 2018 - UIC researchers receive NIH funding to develop a better way to regenerate bone or tissues
August 15, 2018 - Study reveals how immune cells in the brain influence sexual behavior
August 15, 2018 - Researchers move closer to finding potential soft spot in drug-resistant tuberculosis
August 15, 2018 - Real-time dynamic monitoring of cell’s nucleus for effective cancer screening
August 15, 2018 - Lower rates of Medicare preventive care visits found in racial, ethnic minority older adults
August 15, 2018 - Scientists identify stress hormone as key factor in failure of immune system to inhibit leukemia
August 15, 2018 - Cytoplan introduces three new nutritional supplements
August 15, 2018 - Effective hemorrhage control critical for survival after motorsport accidents
August 15, 2018 - Sygnature Discovery announces ambitious expansion plan with addition of Alderley Park facility
August 15, 2018 - Dietary carbohydrates could lead to osteoarthritis, new study finds
August 15, 2018 - Male tobacco smokers have decreased number of cannabinoid CB1 receptors, study reveals
August 15, 2018 - Scientists explore ways for drug therapies to reach deadly brain tumors
August 15, 2018 - Rethinking fundamental rule of stroke care: ‘Time is brain!’
August 15, 2018 - Scientists reveal role of ‘junk DNA’ in cancer dissemination
August 15, 2018 - Google’s DeepMind AI could soon be diagnosing eye conditions
August 15, 2018 - Scientists trick the brain to embody the prosthetic limb
August 15, 2018 - Researchers focus on uncoupling obesity from diabetes
August 15, 2018 - Clinical study shows how EarlySense system effectively detects opioid-induced respiratory depression
August 15, 2018 - A class of proteins shown to be effective in reducing drug-seeking behaviors
August 15, 2018 - FundamentalVR launches first-of-its-kind SaaS software platform for surgical simulation
August 15, 2018 - Gemphire Announces Termination of Phase 2a Clinical Trial of Gemcabene in Pediatric NAFLD
August 15, 2018 - Rheumatoid arthritis in pregnancy associated with low birth weight and premature birth
August 15, 2018 - Study may help increase effectiveness of antibiotics against drug-resistant bacteria
August 15, 2018 - Analyzing resident-to-resident incidents in dementia may hold the key to reducing future fatalities
August 15, 2018 - Robotic walking frame aims to help maintain mobility of older adults
August 15, 2018 - Simple intervention during routine care reduces alcohol consumption in men with HIV
August 15, 2018 - Genetics Home Reference: gout
August 15, 2018 - Scientists ID genesis of disease, focus efforts on shape-shifting tau
August 15, 2018 - OncoThira and NDSU enter into license agreement to develop, market cancer compounds
August 15, 2018 - Scientists unravel the mystery behind ovarian cancer with high-grade serous carcinoma
August 15, 2018 - Common signs that indicate vision problems in children
August 15, 2018 - Removing the cancer label – overhaul in cancer classification proposed
August 15, 2018 - Prams may expose babies and toddlers to more air pollution finds study
August 15, 2018 - Duke researchers track missing T-cells in glioblastoma patients
August 15, 2018 - Cardiac Profiles Up With Exercise, Less Sitting in Early Old Age
August 15, 2018 - Precision medicine offers a glimmer of hope for Alzheimer’s disease
August 15, 2018 - Immunovia’s new blood-based testing platform accurately detects non-small cell lung cancer
Getting to the heart of congenital cardiac defects

Getting to the heart of congenital cardiac defects

image_pdfDownload PDFimage_print
Credit: CC0 Public Domain

Heart defects are the most common type of birth defect, and can be caused by mutations in the gene CHD4. Researchers at the UNC School of Medicine have now revealed key molecular details of how CHD4 mutations lead to heart defects.

The team, in their study published in Proceedings of the National Academy of Sciences this week, found that the CHD4 protein normally works in developing heart muscle cells to repress the production of muscle-filament proteins that are meant to operate in non-heart types of muscle cell. The failure of this repression leads to the development of abnormal, “hybrid” muscle cells that can’t pump blood as efficiently as normal heart cells.

“For patients with congenital heart defects linked to CHD4 mutations, this research helps explain why their hearts don’t work as well as normal, and suggests strategies for therapeutic intervention,” said study senior author Frank Conlon, Ph.D., a professor in the departments of biology and genetics at UNC and a member of the UNC McAllister Heart Institute.

The research was a collaborative effort involving the Conlon Laboratory, the laboratory of Ian Davis, MD, Ph.D., associate professor in UNC’s division of pediatric hematology-oncology, and the laboratory of Paul Wade, Ph.D. at the National Institute of Environmental Health Sciences.

The team, including first author Caralynn M. Wilczewski, a graduate student in the Conlon Laboratory, began by engineering mice whose developing embryos lack CHD4 just in their heart cells. The embryonic mice developed severe cardiac defects midway through gestation and none was born alive. These results confirmed the necessity for CHD4 in heart development.

CHD4, the protein encoded by the CHD4 gene, normally works as part of a multi-protein “machine” that helps regulate gene activity within the nuclei of cells. The researchers therefore conducted a set of experiments to measure and analyze the changes in developing heart-muscle cell gene activity when CHD4 is absent. They found that the CHD4 protein normally binds directly to DNA in a way that represses the activity of genes that encode non-heart muscle proteins. These proteins help make up the springy fibers (myofibrils) that contract and relax when muscles work.

The team determined that when the CHD4 protein is absent, these other, non-cardiac muscle proteins are inappropriately produced in developing heart muscle cells. They become incorporated into the myofibrils in these cells, forming abnormal, hybrid myofibrils that lack the functional properties of the normal heart.

Wilczewski developed an advanced ultrasound technique and used it to record the activity of the tiny hearts developing in mice—organs which in mid-gestation are only about as large as the period at the end of this sentence.

“We observed that the hearts lacking CHD4 and having these abnormal cardiac myofibrils had severely reduced ventricular contractions, indicating a loss of the ability to pump blood normally,” Wilczewski said.

“These findings indicate that normal cardiac development in mice depends on the repression of non-cardiac myofiber proteins in heart muscle cells, to allow the formation of normal cardiac myofibers capable of sustaining normal heart contractions,” Conlon said.

The findings provide the first clear insight into the mechanism of CHD4-related cardiac defects. They also suggest the possibility that restoring the normal repression of non-cardiac myofiber proteins could prevent heart defects in cases where CHD4 is mutated.

The researchers now plan to investigate the ways in which specific human CHD4 mutations lead to cardiac defects.

In addition, they plan to use the new ultrasound technology developed by Wilczewski in further research. “This technology has broad applications for testing models of congenital heart disease,” Conlon said.


Explore further:
Researchers discover the molecular mechanisms that produce the heart’s contractile structure

More information:
Caralynn M. Wilczewski et al, CHD4 and the NuRD complex directly control cardiac sarcomere formation, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1722219115

Journal reference:
Proceedings of the National Academy of Sciences

Provided by:
University of North Carolina Health Care

Tagged with:

About author

Related Articles