Stem cell model reveals gene expression during development of hypothalamus

By Leah Sherwood, The Science Advisory Board assistant editor

November 23, 2021 -- Researchers created an in vitro stem cell model of the hypothalamus to study its development over different stages. In doing so, they identified several genes involved with bodily functions associated with the hypothalamus, including disorders related to sleep and reproduction, according to research published November 19 in Nature Communications.

The in vitro model, created from embryonic stem cells (ESCs), makes it possible to study the genetic architecture of the hypothalamus in three dimensions over time, starting from hypothalamic progenitor cells and culminating in arcuate nucleuslike hypothalamic neurons.

Using the model to investigate genetic regulation of hypothalamic development and function promises to yield insights into the pathogenesis of and susceptibility to disorders related to traits such as body weight and reproductive timing that are associated with the hypothalamus.

"By studying the three-dimensional genomic architecture of these cell models, we can see the dynamic process of how the hypothalamus is formed over different stages of development," said senior study author Struan Grant, PhD, director of the Center for Spatial and Functional Genomics and the Daniel B. Burke Endowed Chair for Diabetes Research at the Children's Hospital of Philadelphia (CHOP). "The information we yielded in this study provides us with more concrete information about diseases that are relevant to hypothalamic function."

The hypothalamus is involved in many functions of the autonomic nervous system and is responsible for maintaining the balance of the human body (homeostasis). As the link between the nervous system and the endocrine system, it governs traits in body weight, emotional responses, reproduction, sleep, and much more.

While research has been done measuring changes in gene expression in the hypothalamus during development -- for instance, genomewide association studies (GWAS) have revealed hundreds of loci associated with the hypothalamus -- questions remain about the effect of GWAS on genes that drive certain traits regulated by the hypothalamus.

Previous efforts to study these issues have been stymied by the sheer inaccessibility of the hypothalamus, which is located in the center of the brain.

In this study, the research team led by Matthew Pahl, PhD, a bioinformatics scientist at the Center for Spatial and Functional Genomics at CHOP, created a three-dimensional in vitro ESC model of the hypothalamus and then used it to characterize the corresponding cis-regulatory elements (cREs), or the noncoding DNA in or near each gene of interest, in hypothalamic neuron differentiation.

The researchers then used RNA sequencing, assay for transpose-accessible chromatin sequencing, and capture C analysis to integrate the data with GWAS loci for various complex traits, which helped them identify multiple candidate effector genes.

"We mapped common GWAS variants associated with AAM [age at menarche], BMI, height, bipolar disorder, sleep, and MDD [major depressive disorder] to putative effector genes via their likely cREs," the authors wrote. "This approach identified both known and novel genes."

For example, using the data generated from the ESC model, the researchers confirmed the role of the brain-derived neurotrophic factor (BDNF) gene in influencing body mass index and obesity risk. The data also implicated the period circadian regulator 2 (PER2) gene in advanced sleep-phase syndrome, a disorder of circadian timing in which the timing of sleep and the peak period of alertness are advanced several hours earlier than the desired and conventional bedtime.

Many of the disorders the researchers looked at can be caused by multiple factors -- for example, body mass index can be affected by variants in genes expressed in the hypothalamus or in fat tissue cells. The findings will help researchers distinguish the context in which the genes operate, thereby informing clinical practice and leading to more personalized treatment options.

All the data generated from the study will be made publicly available, the authors said.

"The data set we derived from this study allows other researchers to determine which diseases or conditions are relevant when doing a genetic workup of the patient," Grant said. "As more information about the hypothalamus is known, that information can be queried against this data set and potentially identify therapeutic targets for multiple disorders."

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