From trans to cis: transcriptional regulatory networks in neocortical development
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Transcriptional mechanisms mediated by the binding of transcription factors (TFs) to cis-acting regulatory elements (CREs) in DNA play crucial roles in directing gene expression. While TFs have been extensively studied, less effort has gone towards the identification and functional characterization of CREs and associated epigenetic modulation. However, owing to methodological and analytical advances, more comprehensive studies of regulatory elements and mechanisms are now possible. We summarize recent progress in integrative analyses of these regulatory components in the development of the cerebral neocortex, the part of the brain involved in cognition and complex behavior. These studies are uncovering not only the underlying transcriptional regulatory networks, but also how these networks are altered across species and in neurological and psychiatric disorders.
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In 12-year-olds, the path length of resting-state networks has a heritability of 42%.
“In 12-year-olds, the path length of resting-state networks has a heritability of 42%155.”
From Imaging structural and functional brain development in early childhood (2018) · cites this paper as [155]
Many genes encoding transcription factors and associated regulatory networks involved in specification and differentiation of different subtypes of neurons and glia are highly conserved across mammals.
“Comparative genomic studies have shown that many of the genes encoding transcription factors and associated regulatory networks involved in the specification and differentiation of different subtypes of neurons and glia are highly conserved across mammals (Nord et al., 2015; Shibata et al., 2015).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Shibata et al., 2015
Spatio-temporal patterns of gene expression are achieved through complex regulatory processes involving several players that function combinatorially.
“The spatio-temporal patterns of gene expression discussed above are achieved through complex regulatory processes involving several players that function in a combinatorial way (Nord et al., 2015; Shibata et al., 2015).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Shibata et al., 2015
Many genes previously implicated in generation and specification of cortical projection neurons and interneurons have well conserved expression gradients and domains among neural stem/progenitor cells in ventricular zone/subventricular zone or neurons in subplate and cortical plate, indicating human neocortical patterning employs many of the same principles observed across mammalian species.
“For instance, many of the genes previously implicated in the generation and specification of distinct subtypes of cortical projection neurons (Leone et al., 2008; Molyneaux et al., 2007; Shibata et al., 2015) and interneurons (Southwell et al., 2014) have well conserved expression gradients and domains among neural stem/progenitor cells in the VZ/SVZ or neurons in the SP and CP (Bayatti et al., 2”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Shibata et al., 2015
Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, play a critical role in regulating spatio-temporal expression patterns.
“Epigenetic mechanisms, acting in concert with trans- and cis-components of the regulatory circuitry, play a critical role in regulating spatio-temporal expression patterns (Maze et al., 2014; Nord et al., 2015; Shibata et al., 2015).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Shibata et al., 2015
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Benton, M. A. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.9 · Cited by 19 · see citing works
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Dynel, M. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.25 · Cited by 17 · see citing works
Ganis, G. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.35 · Cited by 17 · see citing works
RNA-seq analysis of developing olfactory bulb projection neurons
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Direct and indirect gene repression by the ecdysone cascade during mosquito reproductive cycle
Roy, S., Saha, T. T., Ha, J., Banerjee, R., Aksoy, E., Kulkarni, A., & Raikhel, A. S. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2116787119 · Cited by 15 · see citing works
Cux2 expression regulated by Lhx2 in the upper layer neurons of the developing cortex
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Survivin a radiogenetic promoter for glioblastoma viral gene therapy independently from CArG motifs
Naoum, G. E., Zhu, Z. B., Buchsbaum, D. J., Curiel, D. T., & Arafat, W. O. (2017) · Clinical and Translational Medicine · doi:10.1186/s40169-017-0140-y · Cited by 13 · see citing works
Égré, P., & Icard, B. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.27 · Cited by 13 · see citing works
Meyer, K. A., Marquès‐Bonet, T., & Šestan, N. (2017) · Molecular Biology and Evolution · doi:10.1093/molbev/msx076 · Cited by 12 · see citing works
Green, S. P. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.38 · Cited by 11 · see citing works
Fahad, M., Altaf, M. T., Jamil, A., Basıt, A., Aslam, M. M., Liaqat, W., Shah, M. N., Ullah, I., & Mohamed, H. I. (2023) · Transgenic Research · doi:10.1007/s11248-023-00337-x · Cited by 11 · see citing works
Epigenomic landscapes during prefrontal cortex development and aging in rhesus
Ning, C., Wu, X., Zhao, X., Lu, Z., Yao, X., Zhou, T., Yi, L., Sun, Y., Wu, S., Liu, Z., et al. (2024) · National Science Review · doi:10.1093/nsr/nwae213 · Cited by 12 · see citing works
Prospects of Non-Coding Elements in Genomic DNA Based Gene Therapy
Simna, S. P., & Han, Z. (2021) · Current Gene Therapy · doi:10.2174/1566523221666210419090357 · Cited by 11 · see citing works
The Identification and Interpretation of cis-Regulatory Noncoding Mutations in Cancer
Patel, M. B., & Wang, J. (2018) · Microarrays · doi:10.3390/ht8010001 · Cited by 10 · see citing works
Lying, Implicating, and Presupposing
Meibauer, J. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.14 · Cited by 10 · see citing works
Lying and Deception in Politics
Robinson, P., Miller, D., Herring, E., & Bakir, V. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.42 · Cited by 9 · see citing works
Lying and Computational Linguistics
van Deemter, K., & Reiter, E. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.32 · Cited by 8 · see citing works
Mega-enhancers compartmentalize transcriptionally active long genes in the brain
Zhao, Z., Parra, O. A. P., Fujita, S.-I., Musella, F., Alvarado, N. J. S., Alber, F., Yang, Y., & Yamada, T. (2026) · Nature Cell Biology · doi:10.1038/s41556-026-02043-2 · Cited by 7 · see citing works
Meibauer, J. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.19 · Cited by 7 · see citing works
de Martin, X., Oliva, B., & Santpere, G. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae950 · Cited by 5 · see citing works
Lackey, J. A. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.18 · Cited by 6 · see citing works
Jiang, T., Yang, Y., Wu, C., Qu, C., Chen, J.-G., & Cao, H. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.01.053 · Cited by 6 · see citing works
Beier, K. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.15 · Cited by 6 · see citing works
Cohesin regulation of genome organization in mature granule neurons in the mouse cerebellum
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Classic Philosophical Approaches to Lying and Deception
Mahon, J. E. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.2 · Cited by 5 · see citing works
Development of Lying and Cognitive Abilities
Talwar, V. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.30 · Cited by 5 · see citing works
Romero-Morales, A. I., & Gama, V. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.840265 · Cited by 5 · see citing works
Loss of Zmiz1 in Mice Leads to Impaired Cortical Development and Autistic-Like Behaviors
Rajan, K. C., Patel, N., Thurmon, A. N., Kantor, B. L., Lorino, M. G., Tiemroth, A. S., Morrison, V. E., Akumuo, M., Shenoy, A., Blanco-Fernandez, X., et al. (2026) · Biological Psychiatry · doi:10.1016/j.biopsych.2026.01.014 · Cited by 5 · see citing works
Linguistic Approaches to Lying and Deception
Hardin, K. J. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.4 · Cited by 4 · see citing works
Wu, N., Li, J., Zheng, Q., Wu, J., & Xu, W. (2022) · Environmental and Experimental Botany · doi:10.1016/j.envexpbot.2022.105199 · Cited by 4 · see citing works
Sirt6 regulates the proliferation of neural precursor cells and cortical neurogenesis in mice
Wei, Y., Wang, X., Ma, Z., Xiang, P., Liu, G., Yin, B., Hou, L., Shu, P., Liu, W., & Peng, X. (2023) · iScience · doi:10.1016/j.isci.2023.108706 · Cited by 4 · see citing works
Functional Characterization of the MeSSIII-1 Gene and Its Promoter from Cassava
Lü, X., Wang, Y., Zhen, X.-H., Yu, H., Pan, M., Fu, D.-Q., Li, R., Liu, J., Luo, H.-Y., Hu, X., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094711 · Cited by 4 · see citing works
Jary, M. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.8 · Cited by 4 · see citing works
Verma, A., Arya, R., & Brahmachari, V. (2022) · Gene · doi:10.1016/j.gene.2022.146832 · Cited by 4 · see citing works
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Lying, Testimony, and Epistemic Vigilance
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Nishimura, F. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.45 · Cited by 3 · see citing works
Neocortical neurogenesis: a proneural gene perspective
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Lying, Metaphor, and Hyperbole
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From animal to human epigenetics
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Kümmerling‐Meibauer, B. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.44 · Cited by 2 · see citing works
Psycholinguistic Approaches to Lying and Deception
Bott, L. A., & Williams, E. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.5 · Cited by 2 · see citing works
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Lying, Deception, and the Brain
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Epigenetic function in neurodevelopment and cognitive impairment
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The Molecular Landscape of the Developing Human Central Nervous System
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Lemon, R. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.727847917.793557137
Meibauer, J. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.1
Carson, T. L. (2018) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198736578.013.43
- Authors
- Shibata, M., Gulden, F. O., & Sestan, N.
- Affiliations
- Yale University (US)
- Venue
- Trends in Genetics
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 31
- Issue
- 2
- Pages
- 77-87
- ISSN
- 0168-9525 (ISSN-L)
- PMC
- PMC4382006
- OpenAlex
- W2113267995
- Cited by
- 109
- References
- 138
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 6 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 7 · 2018: 57 · 2017: 7 · 2016: 3 · 2015: 3
- FWCI
- 2.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Trends in Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (U01MH103339, P50MH106934, U01MH081896, U01MH105972)
- National Institute of Neurological Disorders and Stroke (R01NS054273)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- transcriptional regulatory networks, cis-regulatory elements, transcription factors, neocortex development, epigenetic regulation, gene expression regulation, species differences, neurological disorders, mental illness
- MeSH terms
- Animals, Mental Disorders, Cell Differentiation, Cell Movement, Gene Expression Regulation, Humans, Nerve Net, Nervous System Diseases, Neuroglia, Neurons, Regulatory Sequences, Nucleic Acid, Transcription, Genetic, Neocortex, Regulatory Elements, Transcriptional, Gene Regulatory Networks, Neurogenesis
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