Nuclear IDH1 Regulates Human Erythropoiesis by Remodeling Chromatin State in a Metabolic Enzyme-Independent Manner

Kernekoncepter

Nuclear IDH1 plays a critical role in maintaining chromatin architecture and gene expression during terminal erythropoiesis, independent of its metabolic enzyme function.

Resumé

The study investigates the role of isocitrate dehydrogenase 1 (IDH1) in human erythropoiesis. Key findings:

1. Knockdown of IDH1 impairs terminal erythroid differentiation, leading to abnormal nuclear morphology and reduced enucleation, which cannot be rescued by reactive oxygen species (ROS) scavengers or α-ketoglutarate (α-KG) supplementation.

2. IDH1 localizes to the nucleus of human erythroid cells, including those from AML/MDS patients with IDH1 mutations, suggesting a nuclear function independent of its metabolic enzyme activity.

3. Nuclear IDH1 deficiency leads to aberrant accumulation and redistribution of specific histone modifications, particularly H3K79me3, which alters chromatin accessibility and gene expression.

4. Integrated analysis of ChIP-seq, ATAC-seq, and RNA-seq data identifies SIRT1 as a key target gene affected by IDH1 deficiency-induced H3K79me3 accumulation.

5. Pharmacological modulation of SIRT1 activity can partially rescue the defects in nuclear morphology and enucleation caused by IDH1 knockdown, confirming SIRT1 as a critical mediator of IDH1's regulatory effects on terminal erythropoiesis.

The study provides novel insights into the non-canonical, chromatin-related functions of the metabolic enzyme IDH1 in regulating human erythroid development, with implications for understanding the pathogenesis of IDH1-associated myeloid disorders.

Statistik

IDH1 deficiency led to a significant decrease in α-KG levels to 20 nmol compared to 35 nmol in control group on day 15.
IDH1 deficiency increased the proportion of euchromatin by 2-3 folds in late erythroblasts compared to control cells.
IDH1 knockdown resulted in 21,169 peaks of H3K79me3, which was significantly larger than 91 peaks of H3K27me2 and 1,740 peaks of H3K9me3.
Around 45% of H3K79me3 peaks were located in promoter regions, compared to ~70% of H3K27me2 and H3K9me3 peaks in distal intergenic regions.

Citater

"IDH1 deficiency led to dramatic accumulation of multi-histone modifications, among which H3K79me3 was identified as the crucial factor, resulting in SIRT1 upregulation and consequently leading to defects in various critical cell events during terminal stage erythropoiesis."
"Our findings suggest synergistic actions of nuclear IDH1 and cytoplasmic on regulation of human erythropoiesis by modulating metabolism and chromatin architecture."
"The findings related to IDH1-H3K79me3-SIRT1 regulatory axis indicates that H3K79me3 and SIRT1 may be targeted for the diagnosis and treatment of diseases with IDH1 mutations."

Vigtigste indsigter udtrukket fra

IDH1 regulates human erythropoiesis by eliciting chromatin state reprogramming in a metabolic enzyme independent manner

by Li,M., Zhang... kl. www.biorxiv.org 06-21-2024

https://www.biorxiv.org/content/10.1101/2024.06.18.599556v1

Dybere Forespørgsler

How might the non-canonical, chromatin-related functions of IDH1 identified in this study be leveraged for the development of novel therapeutic strategies for IDH1-associated myeloid disorders?

The non-canonical, chromatin-related functions of IDH1 identified in this study provide a new avenue for the development of novel therapeutic strategies for IDH1-associated myeloid disorders. By understanding the role of IDH1 in regulating chromatin dynamics and gene expression programs during erythropoiesis, researchers can explore targeted interventions that specifically modulate these pathways to restore normal cellular function in patients with IDH1 mutations.
One potential therapeutic strategy could involve targeting the IDH1-H3K79me3-SIRT1 regulatory axis identified in this study. Since IDH1 deficiency leads to aberrant accumulation of H3K79me3 and subsequent upregulation of SIRT1, inhibitors targeting SIRT1 could be explored as a potential treatment option. By inhibiting SIRT1, it may be possible to reverse the dysregulated gene expression and chromatin states caused by IDH1 deficiency, ultimately restoring normal erythropoiesis in patients with IDH1 mutations.
Furthermore, the identification of nuclear-localized IDH1 and its role in chromatin remodeling opens up the possibility of developing targeted therapies that specifically modulate the non-canonical functions of metabolic enzymes in the nucleus. By targeting these pathways, researchers may be able to develop more effective and precise treatments for IDH1-associated myeloid disorders, potentially improving patient outcomes and quality of life.

How might the non-canonical, chromatin-related functions of IDH1 identified in this study be leveraged for the development of novel therapeutic strategies for IDH1-associated myeloid disorders?

The non-canonical, chromatin-related functions of IDH1 identified in this study provide a new avenue for the development of novel therapeutic strategies for IDH1-associated myeloid disorders. By understanding the role of IDH1 in regulating chromatin dynamics and gene expression programs during erythropoiesis, researchers can explore targeted interventions that specifically modulate these pathways to restore normal cellular function in patients with IDH1 mutations.
One potential therapeutic strategy could involve targeting the IDH1-H3K79me3-SIRT1 regulatory axis identified in this study. Since IDH1 deficiency leads to aberrant accumulation of H3K79me3 and subsequent upregulation of SIRT1, inhibitors targeting SIRT1 could be explored as a potential treatment option. By inhibiting SIRT1, it may be possible to reverse the dysregulated gene expression and chromatin states caused by IDH1 deficiency, ultimately restoring normal erythropoiesis in patients with IDH1 mutations.
Furthermore, the identification of nuclear-localized IDH1 and its role in chromatin remodeling opens up the possibility of developing targeted therapies that specifically modulate the non-canonical functions of metabolic enzymes in the nucleus. By targeting these pathways, researchers may be able to develop more effective and precise treatments for IDH1-associated myeloid disorders, potentially improving patient outcomes and quality of life.

What other nuclear-localized metabolic enzymes might play similar roles in regulating chromatin dynamics and gene expression programs during cellular differentiation and development?

Several other nuclear-localized metabolic enzymes may play similar roles in regulating chromatin dynamics and gene expression programs during cellular differentiation and development. One example is hexokinase 2 (HK2), which has been shown to localize to the nucleus of hematopoietic stem and progenitor cells and influence stem cell function independently of its metabolic function. Nuclear HK2 has been implicated in regulating gene expression, DNA repair, and apoptosis, highlighting its non-canonical roles in cellular processes.
Another example is glyceraldehyde 3-phosphate dehydrogenase (GAPDH), which can translocate to the nucleus and bind to DNA, influencing gene expression and DNA repair mechanisms. Nuclear GAPDH has been shown to play a role in maintaining telomere length and regulating apoptosis, demonstrating its involvement in chromatin dynamics and gene expression regulation.
Overall, these examples suggest that various metabolic enzymes may have non-canonical functions in the nucleus that contribute to the regulation of chromatin dynamics and gene expression programs during cellular differentiation and development.

Could the IDH1-H3K79me3-SIRT1 regulatory axis identified in erythropoiesis be conserved in other cell lineages or developmental contexts, and if so, what are the broader implications for our understanding of metabolic control of epigenetics and cellular identity?

The IDH1-H3K79me3-SIRT1 regulatory axis identified in erythropoiesis may be conserved in other cell lineages or developmental contexts, as similar mechanisms of chromatin remodeling and gene expression regulation are likely to occur in different cell types. The broader implications of this regulatory axis for our understanding of metabolic control of epigenetics and cellular identity are significant.
Firstly, the conservation of this regulatory axis across different cell lineages would suggest a fundamental role for metabolic enzymes in modulating chromatin dynamics and gene expression programs in various cell types. This highlights the interconnectedness of metabolism and epigenetics in regulating cellular identity and function.
Secondly, the identification of H3K79me3 as a critical factor in response to IDH1 deficiency and its impact on SIRT1 expression underscores the importance of specific histone modifications in mediating the effects of metabolic enzymes on chromatin structure. This regulatory axis may provide insights into how metabolic dysregulation can lead to epigenetic changes that contribute to disease pathogenesis.
Overall, the conservation of the IDH1-H3K79me3-SIRT1 regulatory axis in other cell lineages would have broad implications for our understanding of the intricate interplay between metabolism, epigenetics, and cellular identity. It could pave the way for the development of targeted therapies that modulate these pathways to treat a wide range of diseases beyond IDH1-associated myeloid disorders.