Stopping repetitive elements contributes to normal brain development and function

The gene silencing complex HUSH may be implicated in
complex diseases that affect the brain and neurons.
However, its mechanism of action is unclear
.
Researchers at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) have now discovered the target and physiological function
of a component of the HUSH gene silencing complex and its associated proteins in living organisms.
The study, conducted in laboratory mouse models and human brain organoids, linked
the HUSH complex to normal brain development, neuronal personality and connectivity, and mouse behavior.

The Human Silencing Center (HUSH) complex has recently been recognized as key
to silencing repeating genetic elements, including mammalian transposons.
The HUSH complex contains MPP8, a protein
that binds to histone modifications that tag H3K9me3.
In addition, HUSH is known to absorb other proteins
, including the zinc finger protein MORC2.
In humans, mutations affecting MORC2 have been linked
to axonal neuropathy, a type of nerve damage, and neurodevelopmental disorders.
However, little
is known about the physiological functions of MPP8 and MORC2 and how they affect brain health.
So the researchers, led by IMBA senior researcher Astrid Hagelkruys, set out to study the goals and functions of the two proteins in living organisms, in laboratory mouse models, and in
human brain organoids.

The
team of brain development and behavior changes uses a comprehensive in living organism approach including behavioral, motor, developmental, genetic, and transcriptome experiments
.
They found that MPP8 and MORC2A (mice similar to human MORC2) are highly expressed in the brain, and they are only present in
neurons.
"We demonstrated that MPP8 and MORC2A play a role in normal brain development, the normalization of neuronal identity and neuronal connections, and mouse behavior," said
Astrid Hagel Kruys, leader of the project and co-corresponding author of the study.

In addition, after deletion of MPP8 or MORC2A in the mouse nervous system, the brain volume of the mice increased, the brain structure changed, and the transposable factor expression did not undergo significant changes
.
These deletions affected motor function and behavior
in mice.
"So, surprisingly, in live animals, we found that MPP8 and MORC2A act beyond transposable factor regulation," Hagelkruys said
.

The molecular mechanism is reminiscent of gene silencing
so far, and the HUSH complex is involved in transposon regulation
.
"We found that MPP8 and MORC2A inhibit the procadherin gene cluster
in an h3k9me3-dependent manner.
At the protein level, these clusters of procadherin genes form neuronal surface proteins that mediate contact
with other neurons.
Although procadherin is not a transposable factor, some are expressed in the central nervous system in the form of 'repeat-like' gene clusters," Hagelkruys explains
.
In mouse models, MPP8 and MORC2A specifically silenced procadherin clusters
on mouse chromosome 18.
Deleting MPP8 and MORC2A leads to the formation of more synapses in neurons, which may be consistent
with damage to neuronal personality.
In other words, the ability of neurons to
distinguish between "self" and "non-self.
" By expressing different clustered procadherin combinations, neurons acquire a form of "barcode" that allows them to control the formation of
synaptic connections with other neurons.
Thus, by targeting aggregated procadherins, MPP8 and MORC2A ensure that neurons get the right "barcode" and form synapses
only with the right counterparts.

In addition, the team examined the effects
of MPP8 and MORC2 deficiencies on human brain organoids.
Using this stem cell model derived from the human brain, the scientists observed consistent results: the loss of MPP8 or MORC2 led to an increase
in the number of clustered procadherins expressed in organoid neurons at the single-cell level.
This suggests that the absence of these two proteins also disrupts neuronal recognition
in human brain organoids.

Epigenetics
of Brain and Nervous System Diseases Through current work, researchers have discovered the key role
of the HUSH complex in the epigenetic regulation of procadherin expression in the nervous system.
These findings link
inhibition of repeat-like gene elements to mechanistic effects on brain physiology and behavior in mice.
The team's brain organ results suggest that similar effects
may be found in humans.
"The interest of these findings for the fundamental function of the HUSH complex in the brain lies in the significance
of procadherin in neuronal fidelity and brain evolution.
However, this is still largely unknown
.
Dysregulation of clustering procadherin is associated with various neurological and neurodevelopmental diseases, as well as with a variety of mental disorders in humans
.
Therefore, the new findings may help us better understand the epigenetic regulatory mechanisms that control these diseases and provide a new way to
study brain evolution.

The HUSH complex controls brain architecture and protocadherin fidelity