TY - JOUR
T1 - Megakaryocyte lineage development is controlled by modulation of protein acetylation
AU - Bartels, Marije
AU - Govers, Anita
AU - Polak, Roel
AU - Vervoort, Stephin
AU - Van Boxtel, Ruben
AU - Pals, Cornelieke
AU - Bierings, Marc
AU - Van Solinge, Wouter
AU - Egberts, Toine
AU - Nieuwenhuis, Edward
AU - Mokry, Michal
AU - Coffer, Paul James
PY - 2018/4/26
Y1 - 2018/4/26
N2 - 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.
AB - 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.
KW - Cell differentiation
KW - Acetylation
KW - Polyploidy
KW - Red blood cells
KW - Apoptosis
KW - Platelets
KW - Hematology
UR - http://www.scopus.com/inward/record.url?scp=85046011644&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0196400
DO - 10.1371/journal.pone.0196400
M3 - Article
C2 - 29698469
AN - SCOPUS:85046011644
SN - 1932-6203
VL - 13
SP - 1
EP - 20
JO - PLoS ONE
JF - PLoS ONE
IS - 4
M1 - e0196400
ER -