PMID- 38386135
OWN - NLM
STAT- Publisher
LR  - 20240222
IS  - 1559-1182 (Electronic)
IS  - 0893-7648 (Linking)
DP  - 2024 Feb 22
TI  - High Homocysteine-Thiolactone Leads to Reduced MENIN Protein Expression and an 
      Impaired DNA Damage Response: Implications for Neural Tube Defects.
LID - 10.1007/s12035-024-04033-7 [doi]
AB  - DNA damage is associated with hyperhomocysteinemia (HHcy) and neural tube defects 
      (NTDs). Additionally, HHcy is a risk factor for NTDs. Therefore, this study 
      examined whether DNA damage is involved in HHcy-induced NTDs and investigated the 
      underlying pathological mechanisms involved. Embryonic day 9 (E9) mouse 
      neuroectoderm cells (NE4C) and homocysteine-thiolactone (HTL, active metabolite 
      of Hcy)-induced NTD chicken embryos were studied by Western blotting, 
      immunofluorescence. RNA interference or gene overexpression techniques were 
      employed to investigate the impact of Menin expression changes on the DNA damage. 
      Chromatin immunoprecipitation-quantitative polymerase chain reaction was used to 
      investigate the epigenetic regulation of histone modifications. An increase in 
      gammaH2AX (a DNA damage indicator) was detected in HTL-induced NTD chicken embryos 
      and HTL-treated NE4C, accompanied by dysregulation of phospho-Atr-Chk1-nucleotide 
      excision repair (NER) pathway. Further investigation, based on previous research, 
      revealed that disruption of NER was subject to the epigenetic regulation of 
      low-expressed Menin-H3K4me3. Overexpression of Menin or supplementation with 
      folic acid in HTL-treated NE4C reversed the adverse effects caused by high HTL. 
      Additionally, by overexpressing the Mars gene, we tentatively propose a mechanism 
      whereby HTL regulates Menin expression through H3K79hcy, which subsequently 
      influences H3K4me3 modifications, reflecting an interaction between histone 
      modifications. Finally, in 10 human fetal NTDs with HHcy, we detected a decrease 
      in the expression of Menin-H3K4me3 and disorder in the NER pathway, which to some 
      extent validated our proposed mechanism. The present study demonstrated that the 
      decreased expression of Menin in high HTL downregulated H3K4me3 modifications, 
      further weakening the Atr-Chk1-NER pathway, resulting in the occurrence of NTDs.
CI  - (c) 2024. The Author(s).
FAU - Bai, Baoling
AU  - Bai B
AUID- ORCID: 0000-0001-9505-5749
AD  - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital 
      Institute of Pediatrics, Yabao Road 2, Beijing, 100020, China.
FAU - Wan, Chunlei
AU  - Wan C
AD  - Department of Pediatrics, Tongzhou Maternal and Child Health Care Hospital, 
      Beijing, 101101, China.
FAU - Xiao, Zonghui
AU  - Xiao Z
AD  - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital 
      Institute of Pediatrics, Yabao Road 2, Beijing, 100020, China.
FAU - Li, Dan
AU  - Li D
AD  - Department of Pediatrics, Tongzhou Maternal and Child Health Care Hospital, 
      Beijing, 101101, China.
FAU - Liu, Lingyun
AU  - Liu L
AD  - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital 
      Institute of Pediatrics, Yabao Road 2, Beijing, 100020, China.
FAU - Zhang, Kexin
AU  - Zhang K
AD  - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital 
      Institute of Pediatrics, Yabao Road 2, Beijing, 100020, China.
FAU - Zhang, Ting
AU  - Zhang T
AD  - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital 
      Institute of Pediatrics, Yabao Road 2, Beijing, 100020, China. 
      zhangtingcv@126.com.
FAU - Zhang, Qin
AU  - Zhang Q
AD  - Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital 
      Institute of Pediatrics, Yabao Road 2, Beijing, 100020, China. 
      maureenzq@hotmail.com.
LA  - eng
GR  - 81971397/National Natural Science Foundation of China/
GR  - 82171652/National Natural Science Foundation of China/
GR  - 81901167/National Natural Science Foundation of China/
PT  - Journal Article
DEP - 20240222
PL  - United States
TA  - Mol Neurobiol
JT  - Molecular neurobiology
JID - 8900963
SB  - IM
OTO - NOTNLM
OT  - DNA damage response (DDR)
OT  - Histone 3 lysine 4 trimethylation (H3K4me3)
OT  - Histone 3 lysine 79 homocysteinylation (H3K79hcy)
OT  - Homocysteine-thiolactone (HTL)
OT  - Hyperhomocysteinemia (HHcy)
OT  - Men1/Menin
OT  - Neural tube defects
EDAT- 2024/02/22 12:42
MHDA- 2024/02/22 12:42
CRDT- 2024/02/22 11:09
PHST- 2023/09/25 00:00 [received]
PHST- 2024/02/10 00:00 [accepted]
PHST- 2024/02/22 12:42 [medline]
PHST- 2024/02/22 12:42 [pubmed]
PHST- 2024/02/22 11:09 [entrez]
AID - 10.1007/s12035-024-04033-7 [pii]
AID - 10.1007/s12035-024-04033-7 [doi]
PST - aheadofprint
SO  - Mol Neurobiol. 2024 Feb 22. doi: 10.1007/s12035-024-04033-7.