Neuronal MAPT expression is mediated by long-range interactions with cis-regulatory elements
Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved..
Tauopathies are a group of neurodegenerative diseases defined by abnormal aggregates of tau, a microtubule-associated protein encoded by MAPT. MAPT expression is near absent in neural progenitor cells (NPCs) and increases during differentiation. This temporally dynamic expression pattern suggests that MAPT expression could be controlled by transcription factors and cis-regulatory elements specific to differentiated cell types. Given the relevance of MAPT expression to neurodegeneration pathogenesis, identification of such elements is relevant to understanding disease risk and pathogenesis. Here, we performed chromatin conformation assays (HiC & Capture-C), single-nucleus multiomics (RNA-seq+ATAC-seq), bulk ATAC-seq, and ChIP-seq for H3K27ac and CTCF in NPCs and differentiated neurons to nominate candidate cis-regulatory elements (cCREs). We assayed these cCREs using luciferase assays and CRISPR interference (CRISPRi) experiments to measure their effects on MAPT expression. Finally, we integrated cCRE annotations into an analysis of genetic variation in neurodegeneration-affected individuals and control subjects. We identified both proximal and distal regulatory elements for MAPT and confirmed the regulatory function for several regions, including three regions centromeric to MAPT beyond the H1/H2 haplotype inversion breakpoint. We also found that rare and predicted damaging genetic variation in nominated CREs was nominally depleted in dementia-affected individuals relative to control subjects, consistent with the hypothesis that variants that disrupt MAPT enhancer activity, and thereby reduced MAPT expression, may be protective against neurodegenerative disease. Overall, this study provides compelling evidence for pursuing detailed knowledge of CREs for genes of interest to permit better understanding of disease risk.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:111 |
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| Enthalten in: |
American journal of human genetics - 111(2024), 2 vom: 01. Feb., Seite 259-279 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rogers, Brianne B [VerfasserIn] |
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| Links: |
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| Themen: |
Alzheimer disease |
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| Anmerkungen: |
Date Completed 14.02.2024 Date Revised 09.03.2024 published: Print-Electronic UpdateOf: bioRxiv. 2023 Apr 11;:. - PMID 37090552 Citation Status MEDLINE |
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| doi: |
10.1016/j.ajhg.2023.12.015 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM36723243X |
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| 245 | 1 | 0 | |a Neuronal MAPT expression is mediated by long-range interactions with cis-regulatory elements |
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| 500 | |a Date Revised 09.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a UpdateOf: bioRxiv. 2023 Apr 11;:. - PMID 37090552 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Tauopathies are a group of neurodegenerative diseases defined by abnormal aggregates of tau, a microtubule-associated protein encoded by MAPT. MAPT expression is near absent in neural progenitor cells (NPCs) and increases during differentiation. This temporally dynamic expression pattern suggests that MAPT expression could be controlled by transcription factors and cis-regulatory elements specific to differentiated cell types. Given the relevance of MAPT expression to neurodegeneration pathogenesis, identification of such elements is relevant to understanding disease risk and pathogenesis. Here, we performed chromatin conformation assays (HiC & Capture-C), single-nucleus multiomics (RNA-seq+ATAC-seq), bulk ATAC-seq, and ChIP-seq for H3K27ac and CTCF in NPCs and differentiated neurons to nominate candidate cis-regulatory elements (cCREs). We assayed these cCREs using luciferase assays and CRISPR interference (CRISPRi) experiments to measure their effects on MAPT expression. Finally, we integrated cCRE annotations into an analysis of genetic variation in neurodegeneration-affected individuals and control subjects. We identified both proximal and distal regulatory elements for MAPT and confirmed the regulatory function for several regions, including three regions centromeric to MAPT beyond the H1/H2 haplotype inversion breakpoint. We also found that rare and predicted damaging genetic variation in nominated CREs was nominally depleted in dementia-affected individuals relative to control subjects, consistent with the hypothesis that variants that disrupt MAPT enhancer activity, and thereby reduced MAPT expression, may be protective against neurodegenerative disease. Overall, this study provides compelling evidence for pursuing detailed knowledge of CREs for genes of interest to permit better understanding of disease risk | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Alzheimer disease | |
| 650 | 4 | |a MAPT | |
| 650 | 4 | |a enhancer | |
| 650 | 4 | |a gene regulation | |
| 650 | 4 | |a neuron | |
| 650 | 7 | |a Chromatin |2 NLM | |
| 650 | 7 | |a MAPT protein, human |2 NLM | |
| 650 | 7 | |a tau Proteins |2 NLM | |
| 700 | 1 | |a Anderson, Ashlyn G |e verfasserin |4 aut | |
| 700 | 1 | |a Lauzon, Shelby N |e verfasserin |4 aut | |
| 700 | 1 | |a Davis, M Natalie |e verfasserin |4 aut | |
| 700 | 1 | |a Hauser, Rebecca M |e verfasserin |4 aut | |
| 700 | 1 | |a Roberts, Sydney C |e verfasserin |4 aut | |
| 700 | 1 | |a Rodriguez-Nunez, Ivan |e verfasserin |4 aut | |
| 700 | 1 | |a Trausch-Lowther, Katie |e verfasserin |4 aut | |
| 700 | 1 | |a Barinaga, Erin A |e verfasserin |4 aut | |
| 700 | 1 | |a Hall, Paige I |e verfasserin |4 aut | |
| 700 | 1 | |a Knuesel, Matthew T |e verfasserin |4 aut | |
| 700 | 1 | |a Taylor, Jared W |e verfasserin |4 aut | |
| 700 | 1 | |a Mackiewicz, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Roberts, Brian S |e verfasserin |4 aut | |
| 700 | 1 | |a Cooper, Sara J |e verfasserin |4 aut | |
| 700 | 1 | |a Rizzardi, Lindsay F |e verfasserin |4 aut | |
| 700 | 1 | |a Myers, Richard M |e verfasserin |4 aut | |
| 700 | 1 | |a Cochran, J Nicholas |e verfasserin |4 aut | |
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