The human heart is arguably one of the most complex and vital structures of the body. It is also the first organ to develop in a fetus. That’s because it’s needed right away to efficiently transport nutrients and waste throughout the growing embryo. Once formed, the heart will continue to do its same job over the course of one’s life. If the heart does not develop properly, then a person’s health is at great risk.
While we know a lot about the heart, its initial formation isn’t something we know too well. But science is catching up, and newer technologies are allowing researchers a closer look into a multitude of conditions, including those that occur at the very start of life. To understand more about the heart’s earliest stages, to accurately pinpoint any abnormalities or congenital heart defects (CHD), researchers are investigating its epigenetic landscape during development.
While genetic variants and rare sequence modifications have been implicated in birth defects of the heart, they only explain about a third of all cases. The unknown occurrences are suspected to be due to alterations in regulatory sequences and gene expression networks.
To find out if this hypothesis is true, a group of researchers from the University of Connecticut (UConn) School of Medicine set out to characterize chromatin state and gene expression changes during heart development. In their analysis, they were able to identify a well-connected set of heart-specific genes, called “hub genes” and regulators essential for organogenesis as potential disease candidates. Their paper is available to review for free online in Circulation Research.
The team, led by Justin Cotney, Assistant Professor of Genetics and Genome Sciences, discovered their findings by studying a massive dataset of 125,000 control patients’ genomes collected from other studies in the Genome Aggregation Database. As these genes rarely contain any mutations, it was clear to them that they are key for development and cardiac function. According to Cotney, “You can’t be a normal, healthy human with a mutation in these genes.”
Because the heart develops in the embryo within the first four to eight weeks, the researchers isolated this period of time to look at genome activity. Their focus was to look for areas within the nucleus for open chromatin state (euchromatin) as denoted by histone modifications using machine learning.
Chromatin is the complex of DNA and proteins that are packed within the nucleus of a cell. In the formation of chromatin, DNA is tightly wrapped around nuclear proteins called histones. The tighter the DNA is packaged, the less actively transcribed it is. When it is loosely packed and open, it is accessible for transcription. The rearrangement of chromatin is highly implicated in epigenetics. Epigenetic modifications such as methylation and acetylation made to histones can adjust chromatin structure, thereby affecting transcriptional activation or repression.
The machine learning approaches applied in the study allowed the UConn researchers to identify more than 100,000 active regulatory sequences during the early timeframe. Interestingly, around 10% of these were never before marked as active in any other human tissue or growth stage. Their overall investigation identified over 200 novel genes associated with heart development, many of which are likely related to CHD – one of the most common birth defects.
According to Cotney, “These genes were generally being ignored to date, but we’re saying it’s something people should pay attention to.”
Hopefully, the genetic factors flagged in this study will help doctors determine which parts of the genome might be responsible for their patient’s congenital heart condition. Knowing that these genes are part of a network of gene expression elements, it’s reasonable to assess that a single mutation would not be the only cause of CHD. Moreover, the researchers believe that turning off just one regulator would unlikely affect an organism since most regulatory elements are nonessential.
Cotney points out that the datasets provided here are “one of the most comprehensive” for human heart development. Before having this information available, scientists looked at other genes, many of which failed to indicate any underlying problems. The team has filed a patent for their findings and are assured their data will be beneficial to companies using genetic screening for diagnosing heart defects.
“What we found is quite novel,” says Cotney. “We think the combination of these genes will be important in the future for the diagnosis of congenital heart defects.”
Next, the researchers want to examine people affected with CHD to see if these genes are actually mutated. They plan to conduct experiments modifying specific segments of the genome to assess their influence on development.
The information gathered from this study will undoubtedly influence how other research is being conducted on the heart, especially given this organ’s ability to evolve rapidly.
“We knew the power of our method to pull out the relevant biological information.” Cotney acknowledges, “All that information was missing.”
Source: Jennifer VanOudenhove, Tara N. Yankee, Andrea Wilderman, Justin Cotney. Epigenomic and Transcriptomic Dynamics During Human Heart Organogenesis. Circulation Research, 2020; 127 (9)
Reference: Anna Zarra Aldrich. UConn Researcher Identifies Genetic Elements Involved in Heart Development, University of Connecticut. November 3, 2020