Developing brain with DNA strands, symbolizing DOT1L's role in gene expression and brain architecture.

Decoding Brain Development: How DOT1L Shapes Our Cerebral Cortex

Jordan Keane in Science & Nature August 2025 • 4 min read.

"New research illuminates the critical role of the DOT1L protein in neuronal growth and layer formation, paving the way for understanding and potentially addressing developmental disorders."

The development of the cerebral cortex, the brain's command center for higher functions, is a tightly choreographed process orchestrated by transcription factors. These factors activate specific genetic programs that guide cells to their correct location and function within distinct layers of the cortex. However, the mechanisms ensuring the stable inheritance of these functions are only partially understood.

A groundbreaking study sheds light on the crucial role of the DOT1L protein in this process. Researchers have discovered that DOT1L, through its influence on chromatin methylation, plays a key role in regulating cell division, neuronal layer identity, and the expression of genes that shape the developing brain. Understanding how DOT1L functions is critical, as disruptions in this process can lead to neurodevelopmental disorders.

This article explores the findings of the study, explaining how DOT1L promotes progenitor proliferation and primes neuronal layer identity in the developing cerebral cortex. We will delve into the impact of DOT1L on cell fate, gene expression, and the formation of the six distinct layers of the cortex, providing insights into the intricate mechanisms that build our brains.

DOT1L: The Architect of Cortical Layers

Developing brain with DNA strands, symbolizing DOT1L's role in gene expression and brain architecture.

The study reveals that DOT1L acts as a critical regulator of early brain development. By influencing chromatin methylation at H3K79, DOT1L impacts the cell cycle and influences the transcriptional programs that dictate upper layer identity in early progenitors. In essence, DOT1L helps to prevent premature differentiation, ensuring that the right types of neurons are generated at the right time and in the right place.

Specifically, the research highlights the following key functions of DOT1L:

Promoting Progenitor Proliferation: DOT1L increases the expression of genes like Vangl2 and Cenpj, which regulate asymmetric cell division, a process crucial for expanding the pool of progenitor cells.
Maintaining Neuronal Identity: DOT1L supports the expression of genes like SoxB1, essential for progenitor cell identity.
Layer Organization: DOT1L is critical for the proper distribution of deep layer neurons expressing TBR1, CTIP2, and SOX5, as well as the activation of transcriptional programs characteristic of upper layer neurons (Satb2, Pou3f3, Cux2).

The researchers used three different mouse models to demonstrate these functions, showing that DOT1L balances the transcriptional programs necessary for the proper neuronal composition and distribution in the six cortical layers. Furthermore, the data indicates that DOT1L primes upper layer identity in cortical progenitors, particularly influencing the generation of SATB2-expressing upper layer neurons.

Implications and Future Directions

This research provides valuable insights into the intricate mechanisms that govern brain development, highlighting the critical role of DOT1L in ensuring proper cell fate, proliferation, and layer formation. By identifying DOT1L as a key regulator of these processes, the study opens new avenues for understanding and potentially addressing neurodevelopmental disorders.

Further research is needed to fully elucidate the downstream targets of DOT1L and how its activity is regulated during different stages of brain development. Understanding these details will be crucial for developing targeted therapies for disorders linked to DOT1L dysfunction.

Ultimately, this work emphasizes the importance of epigenetic mechanisms in shaping our brains and provides a foundation for future studies aimed at unraveling the complexities of neurodevelopmental disorders.

About this Article -

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This article is based on research published under:

DOI-LINK: 10.1093/nar/gky953, Alternate LINK

Title: Dot1L Promotes Progenitor Proliferation And Primes Neuronal Layer Identity In The Developing Cerebral Cortex

Subject: Genetics

Journal: Nucleic Acids Research

Publisher: Oxford University Press (OUP)

Authors: Henriette Franz, Alejandro Villarreal, Stefanie Heidrich, Pavankumar Videm, Fabian Kilpert, Ivan Mestres, Federico Calegari, Rolf Backofen, Thomas Manke, Tanja Vogel

Published: 2018-10-17

Everything You Need To Know

What role does the DOT1L protein play in brain development, and why is it important?

The DOT1L protein plays a crucial role in regulating cell division, neuronal layer identity, and gene expression, ultimately shaping the developing brain. It achieves this through its influence on chromatin methylation, specifically at H3K79, ensuring the correct types of neurons are generated at the appropriate time and location. Disruptions in DOT1L function can lead to neurodevelopmental disorders, highlighting its importance in brain development.

How does DOT1L influence cell proliferation and neuronal identity in the developing brain?

DOT1L promotes progenitor proliferation by increasing the expression of genes like Vangl2 and Cenpj, which regulate asymmetric cell division, a process vital for expanding the pool of progenitor cells. Additionally, DOT1L maintains neuronal identity by supporting the expression of genes like SoxB1, essential for progenitor cell identity. These functions collectively ensure a sufficient supply of properly specified neurons for the developing cerebral cortex.

How does the DOT1L protein contribute to the organization of the distinct layers of the cerebral cortex?

DOT1L is essential for the correct organization of the six distinct layers of the cerebral cortex. It is critical for the proper distribution of deep layer neurons expressing TBR1, CTIP2, and SOX5. Furthermore, it activates transcriptional programs characteristic of upper layer neurons, such as Satb2, Pou3f3, and Cux2, ensuring the appropriate composition and distribution of neurons within the cortical layers. DOT1L primes upper layer identity in cortical progenitors, particularly influencing the generation of SATB2-expressing upper layer neurons.

What research methods were employed to determine DOT1L's effect on brain development?

The study used different mouse models to demonstrate the functions of the DOT1L protein. By observing the effects of DOT1L on cell division, neuronal layer identity, and gene expression in these models, the researchers were able to confirm that DOT1L balances the transcriptional programs necessary for the proper neuronal composition and distribution in the six cortical layers. The data also showed that DOT1L primes upper layer identity in cortical progenitors, particularly influencing the generation of SATB2-expressing upper layer neurons.

What are the potential implications of identifying DOT1L as a key regulator in brain development, especially concerning neurodevelopmental disorders?

This research identifies DOT1L as a key regulator of cell fate, proliferation, and layer formation during brain development, opening new avenues for understanding and potentially addressing neurodevelopmental disorders. Further research could explore how DOT1L interacts with other transcription factors and epigenetic modifiers, potentially leading to targeted therapies for neurodevelopmental conditions.