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Megakaryocyte lineage development is controlled by modulation of protein acetylation.

ABSTRACT: Treatment with lysine deacetylase inhibitors (KDACi) for haematological malignancies, is accompanied by haematological side effects including thrombocytopenia, suggesting that modulation of protein acetylation affects normal myeloid development, and specifically megakaryocyte development. In the current study, utilising ex-vivo differentiation of human CD34+ haematopoietic progenitor cells, we investigated the effects of two functionally distinct KDACi, valproic acid (VPA), and nicotinamide (NAM), on megakaryocyte differentiation, and lineage choice decisions. Treatment with VPA increased the number of megakaryocyte/erythroid progenitors (MEP), accompanied by inhibition of megakaryocyte differentiation, whereas treatment with NAM accelerated megakaryocyte development, and stimulated polyploidisation. Treatment with both KDACi resulted in no significant effects on erythrocyte differentiation, suggesting that the effects of KDACi primarily affect megakaryocyte lineage development. H3K27Ac ChIP-sequencing analysis revealed that genes involved in myeloid development, as well as megakaryocyte/erythroid (ME)-lineage differentiation are uniquely modulated by specific KDACi treatment. Taken together, our data reveal distinct effects of specific KDACi on megakaryocyte development, and ME-lineage decisions, which can be partially explained by direct effects on promoter acetylation of genes involved in myeloid differentiation.

SUBMITTER: Bartels M

PROVIDER: S-EPMC5919413 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Megakaryocyte lineage development is controlled by modulation of protein acetylation.

Bartels Marije M Govers Anita A Polak Roel R Vervoort Stephin S van Boxtel Ruben R Pals Cornelieke C Bierings Marc M van Solinge Wouter W Egberts Toine T Nieuwenhuis Edward E Mokry Michal M Coffer Paul James PJ

PloS one 20180426 4

Treatment with lysine deacetylase inhibitors (KDACi) for haematological malignancies, is accompanied by haematological side effects including thrombocytopenia, suggesting that modulation of protein acetylation affects normal myeloid development, and specifically megakaryocyte development. In the current study, utilising ex-vivo differentiation of human CD34+ haematopoietic progenitor cells, we investigated the effects of two functionally distinct KDACi, valproic acid (VPA), and nicotinamide (NAM ...[more]

PMID: 29698469

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Project description:Cold stress resulting from chilling and freezing temperatures substantially inhibits plant growth and reduces crop production worldwide. Tremendous research efforts have been focused on elucidating the molecular mechanisms of freezing tolerance in plants. Little is known about the molecular nature of chilling stress responses in plants. Here we found that two allelic mutants in a spliceosome component gene SmEb (smeb-1 and smeb-2) are defective in development and responses to chilling stress. RNA-seq analysis revealed that SmEb controls the splicing of many pre-mRNAs under chilling stress. The intron retentive COP1b splicing variant was dramatically induced by chilling stress in the smeb mutants. This nuclear-depleted COP1b lacks the nuclear speckle-localization capacity, supporting the regulatory role of COP1-HY5 interaction in hypocotyl elongation during chilling stress. Genetic evidence indicates that chilling-sensitive phenotype of the smeb mutants are partially rescued by the hy5 mutation. The transcription factor BES1 shows a dramatic defect in pre-mRNA splicing in the smeb mutants. Ectopic expression of the two BES1 splicing variants enhances the chilling sensitivity of the smeb-1 mutant. Biochemical and genetic analysis showed that CBFs act as negative upstream regulators of SmEb by directly suppressing its transcription. Together, our results demonstrate that proper alternative splicing of pre-mRNAs controlled by the spliceosome component SmEb is critical for plant development and chilling stress responses. Cold stress resulting from chilling and freezing temperatures substantially inhibits plant growth and reduces crop production worldwide. Tremendous research efforts have been focused on elucidating the molecular mechanisms of freezing tolerance in plants. Little is known about the molecular nature of chilling stress responses in plants. Here we found that two allelic mutants in a spliceosome component gene SmEb (smeb-1 and smeb-2) are defective in development and responses to chilling stress. RNA-seq analysis revealed that SmEb controls the splicing of many pre-mRNAs under chilling stress. The intron retentive COP1b splicing variant was dramatically induced by chilling stress in the smeb mutants. This nuclear-depleted COP1b lacks the nuclear speckle-localization capacity, supporting the regulatory role of COP1-HY5 interaction in hypocotyl elongation during chilling stress. Genetic evidence indicates that chilling-sensitive phenotype of the smeb mutants are partially rescued by the hy5 mutation. The transcription factor BES1 shows a dramatic defect in pre-mRNA splicing in the smeb mutants. Ectopic expression of the two BES1 splicing variants enhances the chilling sensitivity of the smeb-1 mutant. Biochemical and genetic analysis showed that CBFs act as negative upstream regulators of SmEb by directly suppressing its transcription. Together, our results demonstrate that proper alternative splicing of pre-mRNAs controlled by the spliceosome component SmEb is critical for plant development and chilling stress responses.

Dataset Information

Megakaryocyte lineage development is controlled by modulation of protein acetylation.

Publications

Megakaryocyte lineage development is controlled by modulation of protein acetylation.

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