Rewiring of human neurodevelopmental gene regulatory programs by human accelerated regions
Open accessAbstract
Human accelerated regions (HARs) are the fastest-evolving regions of the human genome, and many are hypothesized to function as regulatory elements that drive human-specific gene regulatory programs. We interrogate the in vitro enhancer activity and in vivo epigenetic landscape of more than 3,100 HARs during human neurodevelopment, demonstrating that many HARs appear to act as neurodevelopmental enhancers and that sequence divergence at HARs has largely augmented their neuronal enhancer activity. Furthermore, we demonstrate PPP1R17 to be a putative HAR-regulated gene that has undergone remarkable rewiring of its cell type and developmental expression patterns between non-primates and primates and between non-human primates and humans. Finally, we show that PPP1R17 slows neural progenitor cell cycle progression, paralleling the cell cycle length increase seen predominantly in primate and especially human neurodevelopment. Our findings establish HARs as key components in rewiring human-specific neurodevelopmental gene regulatory programs and provide an integrated resource to study enhancer activity of specific HARs.
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NPCs and maturing neurons from human fetal brain tissue at GW 19-20 showed no H3K4me1 or H3K27ac signatures.
“In contrast, NPCs and maturing neurons from human fetal brain tissue (gestational week [GW] 19–20) showed no H3K4me1 or H3K27ac signatures, suggesting that the human HAR202 ortholog does not act as a transcriptional enhancer in the developing human brain (supplementary fig. S8, Supplementary Material online; (Girskis et al. 2021).”
From The Human Accelerated Region HAR202 Controls <i>NPAS3</i> Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences (2024) · cites this paper as Girskis et al. 2021
The Results section, “HARs demonstrate in vivo enhancer features during human brain development” (page unavailable), confirms that the authors tested H3K4me1 and H3K27ac in NPCs and maturing neurons from GW 19–20 fetal brain tissue. It does not report that the HAR202 ortholog lacked those marks; instead, it reports enhancer-associated marks at 504 HARs. The HAR202-specific absence of signatures is therefore not established by our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe human HAR202 ortholog does not act as a transcriptional enhancer in the developing human brain.
“suggesting that the human HAR202 ortholog does not act as a transcriptional enhancer in the developing human brain (supplementary fig. S8, Supplementary Material online; (Girskis et al. 2021).”
From The Human Accelerated Region HAR202 Controls <i>NPAS3</i> Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences (2024) · cites this paper as Girskis et al. 2021
The Results discuss enhancer activity across HARs in neural cells and developing human brain tissue, while the Discussion says 11% of HARs lacked evidence of enhancer activity in the cell types analyzed. Searches for HAR202 and its enhancer activity found no passage identifying whether HAR202 is among them, so our copy does not establish the claim about that specific ortholog. (LLM, conf=0.72)
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Cantsilieris, S., Stessman, H. A. F., Shendure, J., et al. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-6442-0_6 · Cited by 25 · see citing works
Endo, S. (2012) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-396456-4.00004-3 · Cited by 15 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Comparative transcriptomics reveals human-specific cortical features
Jorstad, N. L., Song, J. H. T., Exposito-Alonso, D., Suresh, H., Castro-Pacheco, N., Krienen, F. M., Yanny, A. M., Close, J., Gelfand, E., Long, B., et al. (2023) · Science · doi:10.1126/science.ade9516 · Cited by 208 · see citing works
“PTPRG is located near HARsv2_1818 (chr3:61283266-61283416, hg38), which has decreased enhancer activity from the human sequence compared with that from the orthologous chimpanzee sequence ( 14 ).”
BackgroundMethodInfluentialEarly Alzheimer’s disease pathology in human cortex involves transient cell states
Gazestani, V., Kamath, T., Nadaf, N. M., Dougalis, A., Burris, S. J., Rooney, B., Junkkari, A., Vanderburg, C., Pelkonen, A., Gomez-Budia, M., et al. (2023) · Cell · doi:10.1016/j.cell.2023.08.005 · Cited by 209 · see citing works
Developmental mechanisms underlying the evolution of human cortical circuits
Vanderhaeghen, P., & Polleux, F. (2023) · Nature Reviews Neuroscience · doi:10.1038/s41583-023-00675-z · Cited by 173 · see citing works
Single-cell transcriptomic landscape of the developing human spinal cord
Andersen, J., Thom, N., Shadrach, J. L., Chen, X., Onesto, M. M., Amin, N. D., Yoon, S.-J., Li, L., Greenleaf, W. J., Müller, F., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01311-w · Cited by 61 · see citing works
Caporale, A. L., Cinalli, A. R., Rubinstein, M., & Franchini, L. F. (2024) · Molecular Biology and Evolution · doi:10.1093/molbev/msae186 · Cited by 7 · see citing works
“…al. 2022), ANC516 (HARE5) that interacts with the Fzd8 promoter in the neo-cortex (Boyd et al. 2015), HAR2632 that interacts with the gene PPP1R17 (Girskis et al. 2021) and HAR170 that interacts with the GALNT10 promoter displaying differential activity between the human and the chimpanzee…”
BackgroundInfluential
- Authors
- Girskis, K. M., Stergachis, A. B., DeGennaro, E. M., Doan, R. N., Qian, X., Johnson, M. B., Wang, P. P., Sejourne, G. M., Nagy, M. A., Pollina, E. A., Sousa, A. M. M., Shin, T., Kenny, C. J., Scotellaro, J. L., Debo, B. M., Gonzalez, D. M., Rento, L. M., Yeh, R. C., Song, J. H. T., Beaudin, M., Fan, J., Kharchenko, P. V., Sestan, N., Greenberg, M. E., & Walsh, C. A.
- Affiliations
- Boston Children's Hospital (US)
- University of Washington (US)
- Broad Institute (US)
- Yale University (US)
- Harvard University (US)
- Corresponding author
- Walsh, Christopher A.
- ORCID
- Girskis, Kelly M.
- Stergachis, Andrew B.
- DeGennaro, Ellen M.
- Doan, Ryan N.
- Qian, Xuyu
- Johnson, Matthew B.
- Sejourne, Gabrielle M.
- Nagy, M. Aurel
- Pollina, Elizabeth A.
- Sousa, André M.M.
- Shin, Taehwan
- Kenny, Connor J.
- Gonzalez, Dilenny M.
- Rento, Lariza M.
- Song, Janet H.T.
- Fan, Jean
- Kharchenko, Peter V.
- Greenberg, Michael E.
- Walsh, Christopher A.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2021-10
- Volume
- 109
- Issue
- 20
- Pages
- 3239-3251.e7
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC8542612
- OpenAlex
- W3196312992
- Cited by
- 193
- References
- 83
- Citations by year
- 2026: 31 · 2025: 34 · 2024: 54 · 2023: 49 · 2022: 20 · 2021: 5
- FWCI
- 10.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 384 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (DP5OD029630, 1s10rr028832-01)
- National Institute of Mental Health (P50MH106934, U01MH116488, T32MH020017)
- National Cancer Institute (K00CA222750)
- National Institute of General Medical Sciences (T32GM007753, T32GM007748)
- National Institute of Neurological Disorders and Stroke (R01NS095654, R01NS115965, R01NS032457)
- National Center for Research Resources (S10 RR028832)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090255, P50HD105351)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- human accelerated regions, brain development, enhancer activity, gene regulatory evolution, epigenetic landscape, sequence divergence, primate evolution
- MeSH terms
- Animals, Brain, Pan troglodytes, Biological Evolution, Ferrets, Humans, Macaca, Gene Expression Regulation, Developmental, Evolution, Molecular, Mice, Gene Regulatory Networks, Epigenomics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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