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Tricks that our cells use to express their genes in the brain, and how aging affects this
Published on Sep 22, 20171110 Views
Each RNA in our cells is coated by dozens, if not hundreds of RNA-binding proteins. To understand how these proteins act in our cells, we obtain detailed maps of their RNA binding sites. For this purp
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Tricks that our cells use to express their genes in the brain, and how aging affects this00:00
How do genes get expressed?03:49
How RNA processing affects gene expression? - 105:37
How RNA processing affects gene expression? - 207:32
TDP-43: an RNA-binding protein associated with ALD and FTD11:11
Mutations in RNA-binding proteins cause many diseases12:08
Human induced pluripotent cells (iPSCs) as a disease model13:37
RNA remodelling during motor neurogenesis in human iPS models of ALS - 115:59
RNA remodelling during motor neurogenesis in human iPS models of ALS - 220:54
RNA remodelling during motor neurogenesis in human iPS models of ALS - 321:37
Why might RNA processing be modified in ALS? 22:29
Each RNA interacts with RNA-binding proteins (RBPs)23:16
Dynamics of ribonucleoprotein complexes in development, disease and evolution23:32
iCLIP: nucleotide-resolution crosslinking and immunoprecipitation25:09
TDP-43 regulates splicing in a position-dependent manner26:42
TDP-43 regulates splicing & alternative polyadenylation28:32
TDP-43 binding around the regulated polyA sites30:04
Comparison of TDP-43 binding in FTLD vs. healthy control brain tissue31:18
TDP-43 binds to NEAT1, a long non-coding RNA (lncRNA)31:48
Paraspeckles are assembled by NEAT132:18
Protein-RNA complexes often form membraneless organelles33:00
Occurrence of NEAT1 ncRNA is increased in ALS motor neurons34:28
We studied paraspeckle polyadenylation dynamics during stem cell differentiation35:03
NEAT1 and paraspeckles are induced by differentiation36:11
TDP-43 represses production of the full NEAT1 transcript36:41
TDP-43 binds close to the polyA site in the NEAT1 transcript37:37
TDP-43 promotes formation of the short NEAT1 transcript38:24
Knockout of the internal polyA site allows production of NEAT1v238:52
Knockdown of TDP-43 allows production of NEAT1v239:11
Paraspeckles partially sequester TDP-43 away from mRNAs39:43
Cells overexpressing TDP-43 exhibit a developmental delay40:40
Cells lacking NEAT1 exhibit a developmental delay41:02
TDPTDP-43 knockdown induces the ‘differentiated’ pattern of 3’ end mRNA processing41:28
TDP-43 regulates 3’end processing of SOX2 pre-mRNA42:10
TDP-43 is required for expression of SOX2 protein in pluripotent cells42:57
Cross-regulation of TDP-43 and paraspeckles promote a bistable switch43:10
How are neurodegenerative diseases linked to brain aging?44:38
Splicing of TDP-43-regulated alternative exons in human brain46:00
Alternative splicing affected by aging and/or disease in human brain48:09
Cell types of the brain48:58
Changes in cell-type specific gene expression programmes51:00
Transcriptional hallmarks of human brain aging51:43
Analysis of cell-type specific gene expression upon aging52:53
Neuroinflammation in neurodegeneration54:01
Immunohistochemistry of NeuN-positive cells in the frontal cortex54:25
NeuN-stained image analysis54:47
Analysis of astrocyte and oligodendrocyte-specific genes55:24
Immunohistochemistry of Olig2-positive cells in the frontal cortex56:34
Quantification Olig2-stained images56:43
Summary57:14
Team58:42