Researchers use model of hypothalamus to implicate genes associated with sleep, BMI, puberty
Stem cells help researchers create more complete genomic picture of difficult-to-study part of the brain involved in many key functions

Date:
November 19, 2021
Source:
Children's Hospital of Philadelphia
Summary:
A new study has implicated several genes involved in a variety of
bodily functions associated with the hypothalamus, a notoriously
difficult-to- study region of the brain. The findings could help
clinicians identify potential causes of dysfunction for many
important traits regulated by the hypothalamus, such as sleep,
stress, and reproduction.



FULL STORY ==========================================================================
A study led by researchers at Children's Hospital of Philadelphia (CHOP)
has implicated several genes involved in a variety of bodily functions associated with the hypothalamus, a notoriously difficult-to-study region
of the brain.

The findings could help clinicians identify potential causes of
dysfunction for many important traits regulated by the hypothalamus,
such as sleep, stress, and reproduction.


==========================================================================
The findings were published today in the journal Nature Communications.

The hypothalamus helps maintain health and stable metabolism by
influencing a variety of vital functions, including appetite and
thirst, puberty and reproductive timing, sleep cycles, and body
temperature. However, the hypothalamus is located in the center of
the brain, making it extremely difficult to study the gene regulation associated with these traits.

To overcome that hurdle, the researchers used an embryonic stem
cell (ESC) model to study gene expression during development of the hypothalamus. This model allowed them to study the genetic architecture
first in hypothalamic progenitor cells -- cells prior to their full
development into a hypothalamus - - and then in arcuate nucleus-like hypothalamic neurons. The hypothalamus contains several different
subtypes of neurons, and the researchers integrated results from various genome-wide association studies (GWAS) to implicate genes driving
particular traits regulated by 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
F.A. Grant, PhD, Director of the Center for Spatial and Functional
Genomics and the Daniel B.

Burke Endowed Chair for Diabetes Research at CHOP. "The information
we yielded in this study provides us with more concrete information
about diseases that are relevant to hypothalamic function." Grant and
his collaborators assessed variants associated with puberty, body mass
index, height, bipolar disorder, sleep, and major depressive disorder,
among others. They identified both known and novel genes associated
with these traits. For example, their data confirmed the role of the
BDNF of gene in influencing body mass index and obesity risk. Another
gene of interest identified in the study was PER2, which was implicated
in sleep regulation.

All the data ascertained from this study will be made publicly
available. Many of the disorders studied can be caused by other factors,
so the findings will help researchers distinguish which genes play a more central role in this tissue and in turn inform clinical practice. For
example, body mass index can be affected by variants in genes conferring
their effects in hypothalamus or fat tissue cells, so being able to
distinguish the context in which genes and subsequent tissues or hormones operate can lead to more personalized treatment options.

"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."
This research was supported by the National Center for Research Resources (UL1RR024134) and the National Center for Advancing Translational Sciences (UL1TR000003). This research was also supported in part by the Institute
for Translational Medicine and Therapeutics (ITMAT) Transdisciplinary
Program in Translational Medicine and Therapeutics, the Eunice Kennedy
Shriver National Institute of Child Health (NIH1K99HD099330-01), and
National Institutes of Health grants DK52431-23, P30DK026687-41, R01
HD056465, R01 HG010067, R01 HL143790, and the Daniel B. Burke Endowed
Chair for Diabetes Research.

========================================================================== Story Source: Materials provided by
Children's_Hospital_of_Philadelphia. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Matthew C. Pahl, Claudia A. Doege, Kenyaita M. Hodge, Sheridan H.

Littleton, Michelle E. Leonard, Sumei Lu, Rick Rausch, James
A. Pippin, Maria Caterina De Rosa, Alisha Basak, Jonathan
P. Bradfield, Reza K.

Hammond, Keith Boehm, Robert I. Berkowitz, Chiara Lasconi, Chun Su,
Alessandra Chesi, Matthew E. Johnson, Andrew D. Wells, Benjamin F.

Voight, Rudolph L. Leibel, Diana L. Cousminer, Struan
F. A. Grant. Cis- regulatory architecture of human ESC-derived
hypothalamic neuron differentiation aids in variant-to-gene mapping
of relevant complex traits. Nature Communications, 2021; 12 (1)
DOI: 10.1038/s41467-021- 27001-4 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211119085122.htm

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