-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
Nearly half of the human genome consists of jumping genes containing repetitive sequences, that is, transposons.
Jumping genes have a large number of copies in the genome, and their sequence length is 40 times that of the coding region of the gene.
Jumping genes can be moved from one point on the genome to another by duplication or shearing.
In the process of evolution, most of the jumping genes lost their activity through mutations.
Only a very small part of the jumping genes retain the complete sequence and transposition ability.
Jumping genes provide power for genetic diversity, but also insert normal genes, thereby inactivating host genes and causing various human diseases, such as tumors.
Due to the lack of analysis technology for the sequence of non-gene coding regions, people’s understanding of jumping genes has long been limited to the introduction of mutations by inserting sequences.
Little is known about the biological functions of jumping genes themselves, and they have even been classified as “junk”.
DNA".
But with the development of high-throughput sequencing and CRISPR-based technology, the functions of DNA sequences in non-gene coding regions are being discovered.
On April 8, 2021, the research group of Jian Xu from the Southwestern Medical Center published a research paper titled Silencing of LINE-1 Retrotransposons is a Selective Dependency of Myeloid Leukemia in Nature Genetics.
This study unexpectedly found that retrotransposon LINE-1 with complete transposition activity has a tumor suppressor function in the development of myeloid leukemia, and clarified that LINE-1 activates DNA damage checkpoints through retrotransposition and affects genome stability.
, Thereby inhibiting the proliferation of leukemia cells and promoting the differentiation of leukemia cells.This research not only breaks the traditional understanding of transposons as mutation drivers to promote tumorigenesis, reveals the new tumor suppressor functions of retrotransposons, but also provides new targets for the treatment of leukemia.
Acute Myeloid Leukemia (AML) is a type of hematological malignant tumor with abnormal proliferation of bone marrow hematopoietic stem cells or progenitor cells.
Thanks to the discovery of arsenic and all-trans retinoic acid therapy, one of the subtypes of Acute Promyelocytic Leukemia (APL) has achieved great success in clinical treatment (2,3).
However, the clinical treatment of other types of leukemia is not ideal, and new targets and treatment options are urgently needed.
Dr.
Zhimin Gu of Xu Jian's research group and others have recently discovered a new mechanism for the interaction between epigenetics and tumor metabolism to promote the transformation of hematological tumors.
In this work, the researchers first used CRISPR technology to screen the epigenetic factors dependent on leukemia and found that AML cells are heavily dependent on the core factor MPP8 of the HUSH complex.
Moreover, the dependence of leukemia cells on MPP8 is selective, only limited to AML, and T lymphocyte and B lymphocyte leukemia are not dependent on MPP8.
Knockout of MPP8 significantly inhibits the proliferation of a variety of AML cells, and promotes differentiation and apoptosis.
Further experiments found that the H3K9me3 recognition functional domain chromodomain (CHD) of MPP8 is essential for MPP8 to support the proliferation of leukemia cells.
Knockout of other factors of the HUSH complex also inhibited the proliferation of AML cells and the development of leukemia in immunodeficiency mouse models, suggesting that AML cells require a complete HUSH complex.
In order to study the role of MPP8 and HUSH complex in normal ontogeny and hematopoietic system, the researchers constructed a mouse model of MPP8 knockout.
The researchers first discovered that the mice that constitutively knocked out MPP8 were stunted and had a low birth rate.
At the same time, both males and females were sterile, suggesting that MPP8 is required for normal development, especially for germ cell development.
Knockout of MPP8 specifically in the blood system does not affect normal hematopoiesis.
When the myeloid leukemia fusion gene was introduced into these models, MPP8 deletion significantly inhibited the occurrence of leukemia.
Further experiments confirmed that inducible knockout of MPP8 in established leukemias can also inhibit the development of leukemia, suggesting that MPP8 is an apparent factor necessary for the occurrence and maintenance of AML.
Through ChIP-seq and RNA-seq researchers found that MPP8 mainly binds to non-gene coding regions of chromosomes, and is mainly enriched in the evolutionarily young LINE-1 region.
MPP8 knockout significantly increased the transcription of LINE-1.
According to the analysis of the LINE-1 transposition reporting system, knocking out MPP8 significantly increased the transposition rate of LINE-1.
This is in good agreement with the results reported by the Joanna Wysocka group of Stanford University, suggesting that LINE-1 is the main downstream target gene of MPP8.
To verify whether the activation of LINE-1 mediates the deletion of MPP8, the researchers introduced a myeloid leukemia fusion gene into LINE-1 transgenic mice.
The results show that the activation of LINE-1 can inhibit the progression of leukemia and copy the phenotype of MPP8 deletion.
The researchers further analyzed that whether it is LINE-1 activation induced by MPP8 knockout or LINE-1 activation based on overexpression, it will cause DNA damage in AML cells, activate the DNA damage response, inhibit the proliferation of AML cells, and promote cell differentiation and apoptosis.
Death, thereby inhibiting the occurrence and development of leukemia.
Analysis of clinical data shows that the transcription level of LINE-1 in AML patients is extremely low, and the expression level of LINE-1 is closely related to the prognosis of the patient, while patients with low LINE-1 expression have a poor prognosis.
Patients with low LINE-1 expression levels are more prone to drug resistance and relapse.
These results have been verified in cell and mouse models.
Common leukemia cancer genes can significantly inhibit the transcription of LINE-1, thereby promoting the occurrence and development of leukemia.
In summary, this work revealed for the first time that the jumping gene retrotransposon LINE-1 has a specific tumor suppressor effect, suggesting that the expression level of LINE-1 can be used as a marker for the progression of myeloid leukemia.
This work also clarified the apparent inhibitory mechanism of LINE-1 and provided new ideas for finding possible new targets for myeloid leukemia.
Researcher Xu Jian is the corresponding author of the paper.
Gu Zhimin and Liu Yuxuan are the first and co-first authors respectively.
The main collaborators include researcher John Abrams of Southwestern Medical Center, researcher Zhang Chengcheng and researcher An Wenfeng of South Dakota State University.
Zhang Yuannv, Lu Junhua, Wang Xun, and Deng Mi from Southwest Medical Center participated in the study.
Link to the paper: Open for reprint
Jumping genes have a large number of copies in the genome, and their sequence length is 40 times that of the coding region of the gene.
Jumping genes can be moved from one point on the genome to another by duplication or shearing.
In the process of evolution, most of the jumping genes lost their activity through mutations.
Only a very small part of the jumping genes retain the complete sequence and transposition ability.
Jumping genes provide power for genetic diversity, but also insert normal genes, thereby inactivating host genes and causing various human diseases, such as tumors.
Due to the lack of analysis technology for the sequence of non-gene coding regions, people’s understanding of jumping genes has long been limited to the introduction of mutations by inserting sequences.
Little is known about the biological functions of jumping genes themselves, and they have even been classified as “junk”.
DNA".
But with the development of high-throughput sequencing and CRISPR-based technology, the functions of DNA sequences in non-gene coding regions are being discovered.
On April 8, 2021, the research group of Jian Xu from the Southwestern Medical Center published a research paper titled Silencing of LINE-1 Retrotransposons is a Selective Dependency of Myeloid Leukemia in Nature Genetics.
This study unexpectedly found that retrotransposon LINE-1 with complete transposition activity has a tumor suppressor function in the development of myeloid leukemia, and clarified that LINE-1 activates DNA damage checkpoints through retrotransposition and affects genome stability.
, Thereby inhibiting the proliferation of leukemia cells and promoting the differentiation of leukemia cells.This research not only breaks the traditional understanding of transposons as mutation drivers to promote tumorigenesis, reveals the new tumor suppressor functions of retrotransposons, but also provides new targets for the treatment of leukemia.
Acute Myeloid Leukemia (AML) is a type of hematological malignant tumor with abnormal proliferation of bone marrow hematopoietic stem cells or progenitor cells.
Thanks to the discovery of arsenic and all-trans retinoic acid therapy, one of the subtypes of Acute Promyelocytic Leukemia (APL) has achieved great success in clinical treatment (2,3).
However, the clinical treatment of other types of leukemia is not ideal, and new targets and treatment options are urgently needed.
Dr.
Zhimin Gu of Xu Jian's research group and others have recently discovered a new mechanism for the interaction between epigenetics and tumor metabolism to promote the transformation of hematological tumors.
In this work, the researchers first used CRISPR technology to screen the epigenetic factors dependent on leukemia and found that AML cells are heavily dependent on the core factor MPP8 of the HUSH complex.
Moreover, the dependence of leukemia cells on MPP8 is selective, only limited to AML, and T lymphocyte and B lymphocyte leukemia are not dependent on MPP8.
Knockout of MPP8 significantly inhibits the proliferation of a variety of AML cells, and promotes differentiation and apoptosis.
Further experiments found that the H3K9me3 recognition functional domain chromodomain (CHD) of MPP8 is essential for MPP8 to support the proliferation of leukemia cells.
Knockout of other factors of the HUSH complex also inhibited the proliferation of AML cells and the development of leukemia in immunodeficiency mouse models, suggesting that AML cells require a complete HUSH complex.
In order to study the role of MPP8 and HUSH complex in normal ontogeny and hematopoietic system, the researchers constructed a mouse model of MPP8 knockout.
The researchers first discovered that the mice that constitutively knocked out MPP8 were stunted and had a low birth rate.
At the same time, both males and females were sterile, suggesting that MPP8 is required for normal development, especially for germ cell development.
Knockout of MPP8 specifically in the blood system does not affect normal hematopoiesis.
When the myeloid leukemia fusion gene was introduced into these models, MPP8 deletion significantly inhibited the occurrence of leukemia.
Further experiments confirmed that inducible knockout of MPP8 in established leukemias can also inhibit the development of leukemia, suggesting that MPP8 is an apparent factor necessary for the occurrence and maintenance of AML.
Through ChIP-seq and RNA-seq researchers found that MPP8 mainly binds to non-gene coding regions of chromosomes, and is mainly enriched in the evolutionarily young LINE-1 region.
MPP8 knockout significantly increased the transcription of LINE-1.
According to the analysis of the LINE-1 transposition reporting system, knocking out MPP8 significantly increased the transposition rate of LINE-1.
This is in good agreement with the results reported by the Joanna Wysocka group of Stanford University, suggesting that LINE-1 is the main downstream target gene of MPP8.
To verify whether the activation of LINE-1 mediates the deletion of MPP8, the researchers introduced a myeloid leukemia fusion gene into LINE-1 transgenic mice.
The results show that the activation of LINE-1 can inhibit the progression of leukemia and copy the phenotype of MPP8 deletion.
The researchers further analyzed that whether it is LINE-1 activation induced by MPP8 knockout or LINE-1 activation based on overexpression, it will cause DNA damage in AML cells, activate the DNA damage response, inhibit the proliferation of AML cells, and promote cell differentiation and apoptosis.
Death, thereby inhibiting the occurrence and development of leukemia.
Analysis of clinical data shows that the transcription level of LINE-1 in AML patients is extremely low, and the expression level of LINE-1 is closely related to the prognosis of the patient, while patients with low LINE-1 expression have a poor prognosis.
Patients with low LINE-1 expression levels are more prone to drug resistance and relapse.
These results have been verified in cell and mouse models.
Common leukemia cancer genes can significantly inhibit the transcription of LINE-1, thereby promoting the occurrence and development of leukemia.
In summary, this work revealed for the first time that the jumping gene retrotransposon LINE-1 has a specific tumor suppressor effect, suggesting that the expression level of LINE-1 can be used as a marker for the progression of myeloid leukemia.
This work also clarified the apparent inhibitory mechanism of LINE-1 and provided new ideas for finding possible new targets for myeloid leukemia.
Researcher Xu Jian is the corresponding author of the paper.
Gu Zhimin and Liu Yuxuan are the first and co-first authors respectively.
The main collaborators include researcher John Abrams of Southwestern Medical Center, researcher Zhang Chengcheng and researcher An Wenfeng of South Dakota State University.
Zhang Yuannv, Lu Junhua, Wang Xun, and Deng Mi from Southwest Medical Center participated in the study.
Link to the paper: Open for reprint
