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Editor | xi Hundreds of cell types formed during human development have nearly the same genetic information (DNA), but they can evolve completely different cell shapes and functions
.
Gene transcription regulated by epigenetics participates in determining the specific gene expression profile of each cell type [1,2], and in turn determines its morphology and function
.
Among the many epigenetic mechanisms, the two types of protein complexes PRC1 and PRC2 are involved in the establishment and maintenance of facultative heterochromatin (facultative heterochromatin), which is crucial in the development process [3,4]
.
For a long time, researchers believe that PRC1 and PRC2 are mainly involved in maintaining the inhibited state of gene transcription by regulating histone modification and chromatin structure
.
In recent years, more and more evidence has shown that a class of non-classical PRC1 (ncPRC1) is unexpectedly involved in the activation of gene transcription [5-7], but the specific mechanism of action and its role in the development process need to be further studied
.
On October 11, 2021, the New York University School of Medicine/Howard Hughes Institute of Medicine Danny Reinberg Laboratory (first author is Liu Sanxiong) published an online article titled "NRF1 association with AUTS2" in Molecular Cell magazine.
-Polycomb mediates specific gene activation in the brain" research paper
.
This study elaborated on the molecular mechanism of non-classical PRC1 (ncPRC1) activating gene transcription
.
Danny Reinberg’s lab reported for the first time that the autism-related factor AUTS2 is an important part of non-classical PRC1 (ncPRC1.
3/1.
5).
It is precisely because AUTS2 combines with casein kinase CK2 and transcriptional co-activator P300 that non-classical PRC1 is activated The characteristics of transcription [5]
.
This research is dedicated to exploring this mechanism in more depth
.
Coincidentally, the authors found seven cases with AUTS2 mutations.
Their phenotypes were very different from those caused by complete AUTS2 deletion.
Five of them had AUTS2 mutations (single point mutations in the AUTS2 protein).
Or 8 amino acid deletion) is located in a small functional domain (HX repeat domain) of its protein [Figure 1]
.
More importantly, these patients were clinically diagnosed as Rubinstein-Taybi syndrome (RSTS), a type of multiple organ developmental disorder mainly caused by P300/CBP mutation or deletion before the mutation site was determined by exon sequencing [8]
.
Taking into account the previously reported interaction between AUTS2 and P300, the authors deduced that the HX repeat domain is a key part of mediating this interaction
.
Through the introduction of related mutations in the endogenous AUTS2 gene and a series of molecular biochemical experiments, the authors confirmed that the HX repeat domain mediates the interaction between AUTS2 and P300, and the gene transcription activation caused by this interaction
.
Since the discovered non-classical PRC1 (ncPRC1.
3/1.
5) constituent proteins do not contain functional domains that can bind DNA, the authors further explored how the complex specifically binds to target genes
.
First, the motif analysis of the DNA site bound by AUTS2-PRC1 revealed that the motif of the transcription factor NRF1 binding to DNA was significantly enriched
.
Secondly, approximately 75% of the DNA sites where AUTS2 binds overlap with NRF1 binding sites
.
Finally, by comparing the ChIP-Seq signal of AUTS2 in control cells and NRF1 knockout cells, it was found that the binding of AUTS2 at most of its target sites was significantly reduced or disappeared
.
These evidences fully indicate that the transcription factor NRF1 mediates the localization of AUTS2-PRC1 on chromatin
.
It is worth mentioning that NRF1 conditionally knocked out mice also showed neurodevelopmental disorders similar to RSTS
.
Finally, the author initially explored how the mutation of AUTS2 caused the disease
.
By constructing AUTS2 knockout, endogenous AUTS2 gene mutation or NRF1 knockout mESC, and further inducing neuronal differentiation, combined with the most advanced single-cell sequencing technology (scRNA-Seq, smart-seq3) to compare the final differentiation formation The composition of cell types and differences in gene expression
.
These experiments show that the molecular mechanisms revealed above are essential for the activation of gene transcription required during the differentiation of progenitor to neuron, and provide important clues for understanding how mutations in the AUTS2 HX repeat domain can cause neurodevelopmental disorders (below)
.
(Schematic diagram of the conclusions of the study) In summary, the study elaborated that the transcription factor NRF1 specifically recruits AUTS2-PRC1 on the chromatin, and it is determined by the AUTS2-P300 interaction mediated by the HX repeat domain The transcriptional activation of target genes is essential for the normal development of the brain
.
The corresponding author of the paper is Danny Reinberg, a researcher at New York University School of Medicine/Howard Hughes Medical Institute, and the first author is Liu Sanxiong, a postdoctoral fellow in the laboratory
.
The research was greatly assisted by the laboratory of William B.
Dobyns at Seattle Children's Hospital, and the laboratory of Chai-An Mao at the University of Texas Health Science Center
.
Original link: https://doi.
org/10.
1016/j.
molcel.
2021.
09.
020 Reference 1.
Li, E.
Chromatin modification and epigenetic reprogramming in mammalian development.
Nat Rev Genet 3, 662–673 (2002).
2 .
Perino, M.
& Veenstra, GJC Chromatin Control of Developmental Dynamics and Plasticity.
Developmental Cell 38, 610–620 (2016).
3.
Trojer, P.
& Reinberg, D.
Facultative Heterochromatin: Is There a Distinctive Molecular Signature? Molecular Cell 28, 1–13 (2007).
4.
Schuettengruber, B.
, Bourbon, H.
-M.
, Di Croce, L.
& Cavalli, G.
Genome Regulation by Polycomb and Trithorax: 70 Years and Counting.
Cell 171, 34–57 (2017).
5.
Gao, Z.
et al.
An AUTS2–Polycomb complex activates gene expression in the CNS.
Nature 516, 349–354 (2014).
6.
Cohen, I.
et al.
PRC1 Fine- tunes Gene Repression and Activation to Safeguard Skin Development and Stem Cell Specification.
Cell Stem Cell 22,726-739.
e7 (2018).
7.
Loubiere, V.
, Papadopoulos, GL, Szabo, Q.
, Martinez, A.
-M.
& Cavalli, G.
Widespread activation of developmental gene expression characterized by PRC1-dependent chromatin looping .
Science Advances 6, eaax4001 (2020).
8.
Stevens, CA Rubinstein-Taybi Syndrome.
in GeneReviews® (eds.
Adam, MP et al.
) (University of Washington, Seattle, 1993).
.
Gene transcription regulated by epigenetics participates in determining the specific gene expression profile of each cell type [1,2], and in turn determines its morphology and function
.
Among the many epigenetic mechanisms, the two types of protein complexes PRC1 and PRC2 are involved in the establishment and maintenance of facultative heterochromatin (facultative heterochromatin), which is crucial in the development process [3,4]
.
For a long time, researchers believe that PRC1 and PRC2 are mainly involved in maintaining the inhibited state of gene transcription by regulating histone modification and chromatin structure
.
In recent years, more and more evidence has shown that a class of non-classical PRC1 (ncPRC1) is unexpectedly involved in the activation of gene transcription [5-7], but the specific mechanism of action and its role in the development process need to be further studied
.
On October 11, 2021, the New York University School of Medicine/Howard Hughes Institute of Medicine Danny Reinberg Laboratory (first author is Liu Sanxiong) published an online article titled "NRF1 association with AUTS2" in Molecular Cell magazine.
-Polycomb mediates specific gene activation in the brain" research paper
.
This study elaborated on the molecular mechanism of non-classical PRC1 (ncPRC1) activating gene transcription
.
Danny Reinberg’s lab reported for the first time that the autism-related factor AUTS2 is an important part of non-classical PRC1 (ncPRC1.
3/1.
5).
It is precisely because AUTS2 combines with casein kinase CK2 and transcriptional co-activator P300 that non-classical PRC1 is activated The characteristics of transcription [5]
.
This research is dedicated to exploring this mechanism in more depth
.
Coincidentally, the authors found seven cases with AUTS2 mutations.
Their phenotypes were very different from those caused by complete AUTS2 deletion.
Five of them had AUTS2 mutations (single point mutations in the AUTS2 protein).
Or 8 amino acid deletion) is located in a small functional domain (HX repeat domain) of its protein [Figure 1]
.
More importantly, these patients were clinically diagnosed as Rubinstein-Taybi syndrome (RSTS), a type of multiple organ developmental disorder mainly caused by P300/CBP mutation or deletion before the mutation site was determined by exon sequencing [8]
.
Taking into account the previously reported interaction between AUTS2 and P300, the authors deduced that the HX repeat domain is a key part of mediating this interaction
.
Through the introduction of related mutations in the endogenous AUTS2 gene and a series of molecular biochemical experiments, the authors confirmed that the HX repeat domain mediates the interaction between AUTS2 and P300, and the gene transcription activation caused by this interaction
.
Since the discovered non-classical PRC1 (ncPRC1.
3/1.
5) constituent proteins do not contain functional domains that can bind DNA, the authors further explored how the complex specifically binds to target genes
.
First, the motif analysis of the DNA site bound by AUTS2-PRC1 revealed that the motif of the transcription factor NRF1 binding to DNA was significantly enriched
.
Secondly, approximately 75% of the DNA sites where AUTS2 binds overlap with NRF1 binding sites
.
Finally, by comparing the ChIP-Seq signal of AUTS2 in control cells and NRF1 knockout cells, it was found that the binding of AUTS2 at most of its target sites was significantly reduced or disappeared
.
These evidences fully indicate that the transcription factor NRF1 mediates the localization of AUTS2-PRC1 on chromatin
.
It is worth mentioning that NRF1 conditionally knocked out mice also showed neurodevelopmental disorders similar to RSTS
.
Finally, the author initially explored how the mutation of AUTS2 caused the disease
.
By constructing AUTS2 knockout, endogenous AUTS2 gene mutation or NRF1 knockout mESC, and further inducing neuronal differentiation, combined with the most advanced single-cell sequencing technology (scRNA-Seq, smart-seq3) to compare the final differentiation formation The composition of cell types and differences in gene expression
.
These experiments show that the molecular mechanisms revealed above are essential for the activation of gene transcription required during the differentiation of progenitor to neuron, and provide important clues for understanding how mutations in the AUTS2 HX repeat domain can cause neurodevelopmental disorders (below)
.
(Schematic diagram of the conclusions of the study) In summary, the study elaborated that the transcription factor NRF1 specifically recruits AUTS2-PRC1 on the chromatin, and it is determined by the AUTS2-P300 interaction mediated by the HX repeat domain The transcriptional activation of target genes is essential for the normal development of the brain
.
The corresponding author of the paper is Danny Reinberg, a researcher at New York University School of Medicine/Howard Hughes Medical Institute, and the first author is Liu Sanxiong, a postdoctoral fellow in the laboratory
.
The research was greatly assisted by the laboratory of William B.
Dobyns at Seattle Children's Hospital, and the laboratory of Chai-An Mao at the University of Texas Health Science Center
.
Original link: https://doi.
org/10.
1016/j.
molcel.
2021.
09.
020 Reference 1.
Li, E.
Chromatin modification and epigenetic reprogramming in mammalian development.
Nat Rev Genet 3, 662–673 (2002).
2 .
Perino, M.
& Veenstra, GJC Chromatin Control of Developmental Dynamics and Plasticity.
Developmental Cell 38, 610–620 (2016).
3.
Trojer, P.
& Reinberg, D.
Facultative Heterochromatin: Is There a Distinctive Molecular Signature? Molecular Cell 28, 1–13 (2007).
4.
Schuettengruber, B.
, Bourbon, H.
-M.
, Di Croce, L.
& Cavalli, G.
Genome Regulation by Polycomb and Trithorax: 70 Years and Counting.
Cell 171, 34–57 (2017).
5.
Gao, Z.
et al.
An AUTS2–Polycomb complex activates gene expression in the CNS.
Nature 516, 349–354 (2014).
6.
Cohen, I.
et al.
PRC1 Fine- tunes Gene Repression and Activation to Safeguard Skin Development and Stem Cell Specification.
Cell Stem Cell 22,726-739.
e7 (2018).
7.
Loubiere, V.
, Papadopoulos, GL, Szabo, Q.
, Martinez, A.
-M.
& Cavalli, G.
Widespread activation of developmental gene expression characterized by PRC1-dependent chromatin looping .
Science Advances 6, eaax4001 (2020).
8.
Stevens, CA Rubinstein-Taybi Syndrome.
in GeneReviews® (eds.
Adam, MP et al.
) (University of Washington, Seattle, 1993).
