Functional analysis of human-specific LINC01876 in brain development and its correlation to Major depressive disorder
(2022) MOBN03 20212Degree Projects in Molecular Biology
- Abstract
- In addition to its complex structure, the cerebral cortex has multiple functions exclusive to humans. Unfortunately, it also plays a crucial role in multiple neurodevelopmental and psychiatric disorders. Although we know very little about human-specific gene regulatory mechanisms during brain development, non-coding RNAs are evolutionarily non-conserved, evolve faster, and are highly expressed in neurons, so they are considered to be an important factor in human specific brain development. Using RNA sequencing analysis from human and chimpanzee forebrain neuronal precursors, we determined that LINC01876 is expressed in human beings but not in chimpanzees. Furthermore, an SNP in LINC01876 is associated with the neuropsychiatric disease of... (More)
- In addition to its complex structure, the cerebral cortex has multiple functions exclusive to humans. Unfortunately, it also plays a crucial role in multiple neurodevelopmental and psychiatric disorders. Although we know very little about human-specific gene regulatory mechanisms during brain development, non-coding RNAs are evolutionarily non-conserved, evolve faster, and are highly expressed in neurons, so they are considered to be an important factor in human specific brain development. Using RNA sequencing analysis from human and chimpanzee forebrain neuronal precursors, we determined that LINC01876 is expressed in human beings but not in chimpanzees. Furthermore, an SNP in LINC01876 is associated with the neuropsychiatric disease of Major Depressive Disorder. We then sought to investigate the role of LINC01876 in human brain development. We observed that knocking down this lncRNA with CRISPRi caused differential expression of multiple genes in forebrain neuronal precursors and caused phenotypic changes in 3D brain organoid models. Interestingly, we determined that LINC01876 is only expressed during brain development in vivo, but not during adulthood, as the transposable element located in its promoter region gets silenced. Further investigation is being done to analyze how LINC01876 affects brain development and the correlation between LINC01876 and Major Depressive disorder. (Less)
- Popular Abstract
- What makes us Humans? LINC between Human and Chimpanzee brain
Humans and Chimpanzees are the most closely related primate species. Since the divergence between the human and chimpanzee ancestors, many genetic changes occurred specific to each of the species independent of one another. The human brain is larger and more complex in functionality compared to that of the chimpanzee brain. Despite clear evidence pointing towards the increased complexity of the human brain, very little is known about the human-specific gene machinery regulating brain development. Most of the current knowledge about brain development is obtained from genes that can give rise to proteins. However, these genes tend to be sparse in the human genome and also... (More) - What makes us Humans? LINC between Human and Chimpanzee brain
Humans and Chimpanzees are the most closely related primate species. Since the divergence between the human and chimpanzee ancestors, many genetic changes occurred specific to each of the species independent of one another. The human brain is larger and more complex in functionality compared to that of the chimpanzee brain. Despite clear evidence pointing towards the increased complexity of the human brain, very little is known about the human-specific gene machinery regulating brain development. Most of the current knowledge about brain development is obtained from genes that can give rise to proteins. However, these genes tend to be sparse in the human genome and also evolutionarily conserved making them show sequence similarity among species. Therefore, we decided to study genes that tend to evolve at a faster rate and show less conservation among species. These genes do not give rise to proteins and were initially thought to be junk. They are called non-coding genes which give rise to non-coding RNA (ncRNA). Recent evidence indicates that ncRNAs indeed, play a very important role in human brain development but how? This is the question we aim to answer.
One family of ncRNAs called the long non-coding RNAs or lncRNAs are highly expressed in the neurons. They tend to evolve faster and are less evolutionarily conserved. These lncRNAs can function to regulate the expression of the nearby genes or can possess a wide range of functions throughout the cell. The precise role lncRNAs have in human brain development remains unknown.
We were able to identify a lncRNA called LINC01876 that is expressed in humans and not in the chimpanzees. The level of LINC01876 expression varied in the individuals containing a substitution in one nucleotide that acted as one of the risk parameters in Major Depressive Disorder (MDD). To further characterize the functions of LINC01876 in human-specific brain development, the expression of the latter was suppressed. By doing so, we observed the changes it caused in the expression of other genes.
To study the effects caused due to the inhibition of LINC01876 we grew brain organoids to mirror the in vivo development of the human brain. Brain organoids were developed from cell lines with LINC01876 expression and from those that lacked the expression. The organoids developed from cell lines that lacked LINC01876 expression were smaller in size compared to those of the organoids with LINC01876 expression. This reflected the size differences between regular chimpanzees and the human brain. The findings of this study shine a light on the role of LINC01876 in early human brain development and could pave way for new studies to understand if ncRNAs could be the reason for humans being so different from other closely related primate species.
Master’s Degree Project in Molecular Biology, Molecular Genetics & Biotechnology.
60 credits.
Department of Biology, Lund University
Supervisors: Prof. Johan Jakobsson, Dr. Diahann Atacho
Molecular Neurogenetics, Wallenberg Neurocentrum, BMC (Lund University). (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9103389
- author
- Vinod, Meghna
- supervisor
- organization
- course
- MOBN03 20212
- year
- 2022
- type
- H2 - Master's Degree (Two Years)
- subject
- language
- English
- id
- 9103389
- date added to LUP
- 2022-11-21 14:12:15
- date last changed
- 2022-11-21 14:12:15
@misc{9103389,
abstract = {{In addition to its complex structure, the cerebral cortex has multiple functions exclusive to humans. Unfortunately, it also plays a crucial role in multiple neurodevelopmental and psychiatric disorders. Although we know very little about human-specific gene regulatory mechanisms during brain development, non-coding RNAs are evolutionarily non-conserved, evolve faster, and are highly expressed in neurons, so they are considered to be an important factor in human specific brain development. Using RNA sequencing analysis from human and chimpanzee forebrain neuronal precursors, we determined that LINC01876 is expressed in human beings but not in chimpanzees. Furthermore, an SNP in LINC01876 is associated with the neuropsychiatric disease of Major Depressive Disorder. We then sought to investigate the role of LINC01876 in human brain development. We observed that knocking down this lncRNA with CRISPRi caused differential expression of multiple genes in forebrain neuronal precursors and caused phenotypic changes in 3D brain organoid models. Interestingly, we determined that LINC01876 is only expressed during brain development in vivo, but not during adulthood, as the transposable element located in its promoter region gets silenced. Further investigation is being done to analyze how LINC01876 affects brain development and the correlation between LINC01876 and Major Depressive disorder.}},
author = {{Vinod, Meghna}},
language = {{eng}},
note = {{Student Paper}},
title = {{Functional analysis of human-specific LINC01876 in brain development and its correlation to Major depressive disorder}},
year = {{2022}},
}