scholarly journals Histone Epigenetic Signatures in Embryonic Limb Interdigital Cells Fated to Die

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 911
Author(s):  
Cristina Sanchez-Fernandez ◽  
Carlos I. Lorda-Diez ◽  
Cristina Duarte-Olivenza ◽  
Juan M. Hurle ◽  
Juan A. Montero
Keyword(s):  
Dna Damage ◽  
Histone Deacetylase ◽  
Trichostatin A ◽  
Degradation Process ◽  
Open Chromatin ◽  
Massive Cell Death ◽  
Histone Deacetylase Inhibitor Trichostatin ◽  
Embryonic Limb ◽  
Transcriptional Changes ◽  
Epigenetic Signatures

During limb formation in vertebrates with free digits, the interdigital mesoderm is eliminated by a massive degeneration process that involves apoptosis and cell senescence. The degradation process is preceded by intense DNA damage in zones located close to methylated DNA, accompanied by the activation of the DNA repair response. In this study, we show that trimethylated histone 3 (H3K4me3, H3K9me3, and H3K27me3) overlaps with zones positive for 5mC in the nuclei of interdigital cells. This pattern contrasts with the widespread distribution of acetylated histones (H3K9ac and H4ac) and the histone variant H3.3 throughout the nucleoplasm. Consistent with the intense labeling of acetylated histones, the histone deacetylase genes Hdac1, Hdac2, Hdac3, and Hdac8, and at a more reduced level, Hdac10, are expressed in the interdigits. Furthermore, local treatments with the histone deacetylase inhibitor trichostatin A, which promotes an open chromatin state, induces massive cell death and transcriptional changes reminiscent of, but preceding, the physiological process of interdigit remodeling. Together, these findings suggest that the epigenetic profile of the interdigital mesoderm contributes to the sensitivity to DNA damage that precedes apoptosis during tissue regression.

scholarly journals NuA4 Subunit Yng2 Function in Intra-S-Phase DNA Damage Response

2002 ◽  
Vol 22 (23) ◽  
pp. 8215-8225 ◽  
Author(s):  
John S. Choy ◽  
Stephen J. Kron
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Histone Acetylation ◽  
Trichostatin A ◽  
S Phase ◽  
Open Chromatin ◽  
Histone H4 ◽  
Histone H4 Acetylation ◽  
Histone Deacetylase Inhibitor Trichostatin ◽  
Nucleosomal Histone

ABSTRACT While regulated transcription requires acetylation of histone N-terminal tails to promote an open chromatin conformation, a similar role for histone acetylation in DNA replication and/or repair remains to be established. Cells lacking the NuA4 subunit Yng2 are viable but critically deficient for genome-wide nucleosomal histone H4 acetylation. We found that yng2 mutants are specifically sensitized to DNA damage in S phase induced by cdc8 or cdc9 mutations, hydroxyurea, camptothecin, or methylmethane sulfonate (MMS). In yng2, MMS treatment causes a persistent Mec1-dependent intra-S-phase checkpoint delay characterized by slow DNA repair. Restoring H4 acetylation with the histone deacetylase inhibitor trichostatin A promotes checkpoint recovery. In turn, mutants lacking the histone H3-specific acetyltransferase GCN5 are similarly sensitive to intra-S-phase DNA damage. The inviability of gcn5 yng2 double mutants suggests overlapping roles for H3 and H4 acetylation in DNA replication and repair. Paradoxically, haploid yng2 mutants do not tolerate mutations in genes important for nonhomologous end joining repair yet remain proficient for homologous recombination. Our results implicate nucleosomal histone acetylation in maintaining genomic integrity during chromosomal replication.

scholarly journals Impact of the histone deacetylase inhibitor trichostatin A on active uptake, volume-sensitive release of taurine, and cell fate in human ovarian cancer cells

2020 ◽  
Vol 318 (3) ◽  
pp. C581-C597
Author(s):  
Ian Henry Lambert ◽  
Dorthe Nielsen ◽  
Stefan Stürup
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Trichostatin A ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Caspase 9 ◽  
Deacetylase Inhibitor ◽  
Histone Deacetylase Inhibitor Trichostatin

The histone deacetylase inhibitor trichostatin A (TSA) reduces cell viability in cisplatin-sensitive (A2780WT) and cisplatin-resistant (A2780RES) human ovarian cancer cells due to progression of apoptosis (increased caspase-9 activity), autophagy (increased LC3-II expression), and cell cycle arrest (increased p21 expression). The TSA-mediated effect on p21 and caspase-9 is mainly p53 independent. Cisplatin increases DNA-damage (histone H2AX phosphorylation) in A2780WT cells, whereas cisplatin, due to reduced uptake [inductively coupled-plasma-mass spectrometry (Pt) analysis], has no DNA-damaging effect in A2780RES cells. TSA has no effect on cisplatin accumulation or cisplatin-induced DNA-damage in A2780WT/A2780RES cells. Tracer technique indicates that TSA inhibits the volume-sensitive organic anion channel (VSOAC) in A2780WT/A2780RES cells and that the activity is restored by exogenous H2O2. As TSA reduces NOX4 mRNA accumulation and concomitantly increases catalase mRNA/protein accumulation, we suggest that TSA increases the antioxidative defense in A2780 cells. Inhibition of the kinase mTOR (rapamycin, palomid, siRNA), which is normally associated with cell growth, reduces VSOAC activity synergistically to TSA. However, as TSA increases mTOR activity (phosphorylation of 4EBP1, S6 kinase, S6, ULK1, SGK1), the effect of TSA on VSOAC activity does not reflect the shift in mTOR signaling. Upregulation of the protein expression and activity of the taurine transporter (TauT) is a phenotypic characteristic of A2780RES cells. However, TSA reduces TauT protein expression in A2780RES cells and activity to values seen in A2780WT cells. It is suggested that therapeutic benefits of TSA in A2780 do not imply facilitation of cisplatin uptake but more likely a synergistic activation of apoptosis/autophagy and reduced TauT activity.

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