CRTC1 gene is differentially methylated in the human hippocampus in Alzheimer's disease.
BACKGROUND
CRTC1 (CREB regulated transcription coactivator 1) gene plays a role in synaptic plasticity, learning and long-term memory formation in the hippocampus. Recently, CRTC1 has been shown to be downregulated in Alzheimer's disease (AD). Nevertheless, the mechanisms underlying CRTC1 dysregulation in AD remain unclear.


METHODS
To understand better the epigenetic mechanisms regulating CRTC1 expression that may be altered in AD, we profiled DNA methylation at CpG site resolution by bisulfite cloning sequencing in two promoter regions (referred to as Prom1 and Prom2) of the CRTC1 gene in human hippocampus from controls and AD cases. Next, we correlated DNA methylation levels with AD-related pathology, i.e., β-amyloid and phosphorylated-tau (p-tau) burden and also measured CRTC1 mRNA levels by RT-qPCR.


RESULTS
Methylation levels were lower in AD cases as compared to controls within both promoter regions (Prom1: 0.95% vs. 5%, p-value < 0.01 and Prom2: 2.80% vs. 17.80%, p-value < 0.001). Interestingly, CRTC1 methylation levels inversely correlated with AD-related neuropathological changes, particularly with p-tau deposition (rSpearman = -0.903, p < 0.001). Moreover, a 1.54-fold decrease in CRTC1 mRNA levels was observed in hippocampus of AD cases compared to controls (p < 0.05) supporting the notion that CRTC1 is downregulated in the AD hippocampus.


CONCLUSIONS
DNA methylation levels within two distinct promoter regions of the CRTC1 gene were decreased in human hippocampus affected by AD compared with controls and methylation within Prom1 showed a strong inverse correlation with p-tau deposition. Further studies are guaranteed to elucidate the precise role that CRTC1 methylation plays in AD pathophysiology.
NeuroEpigenetics Laboratory, Navarrabiomed- IdiSNA (Navarra Institute for Health Research), c/ Irunlarrea, 3, Pamplona, Navarra, 31008, Spain. maitemendilab@gmail.com.|Department of Neurology, Complejo Hospitalario de Navarra- IdiSNA (Navarra Institute for Health Research), Pamplona, Navarra, 31008, Spain. maitemendilab@gmail.com.
Maite
M
Mendioroz
NeuroEpigenetics Laboratory, Navarrabiomed- IdiSNA (Navarra Institute for Health Research), c/ Irunlarrea, 3, Pamplona, Navarra, 31008, Spain.
Naiara
N
Celarain
Department of Neurology, Complejo Hospitalario de Navarra- IdiSNA (Navarra Institute for Health Research), Pamplona, Navarra, 31008, Spain.
Miren
M
Altuna
NeuroEpigenetics Laboratory, Navarrabiomed- IdiSNA (Navarra Institute for Health Research), c/ Irunlarrea, 3, Pamplona, Navarra, 31008, Spain.|Department of Neurology, Complejo Hospitalario de Navarra- IdiSNA (Navarra Institute for Health Research), Pamplona, Navarra, 31008, Spain.
Javier
J
Sánchez-Ruiz de Gordoa
Department of Pathology, Complejo Hospitalario de Navarra- IdiSNA (Navarra Institute for Health Research), Pamplona, Navarra, 31008, Spain.
María Victoria
MV
Zelaya
NeuroEpigenetics Laboratory, Navarrabiomed- IdiSNA (Navarra Institute for Health Research), c/ Irunlarrea, 3, Pamplona, Navarra, 31008, Spain.
Miren
M
Roldán
Department of Neurology, Complejo Hospitalario de Navarra- IdiSNA (Navarra Institute for Health Research), Pamplona, Navarra, 31008, Spain.
Idoya
I
Rubio
NeuroEpigenetics Laboratory, Navarrabiomed- IdiSNA (Navarra Institute for Health Research), c/ Irunlarrea, 3, Pamplona, Navarra, 31008, Spain.|Department of Neurology, Complejo Hospitalario de Navarra- IdiSNA (Navarra Institute for Health Research), Pamplona, Navarra, 31008, Spain.
Rosa
R
Larumbe
Department of Neurology, Complejo Hospitalario de Navarra- IdiSNA (Navarra Institute for Health Research), Pamplona, Navarra, 31008, Spain.
María Elena
ME
Erro
NeuroEpigenetics Laboratory, Navarrabiomed- IdiSNA (Navarra Institute for Health Research), c/ Irunlarrea, 3, Pamplona, Navarra, 31008, Spain.|Hospital García-Orcoyen, Estella, Navarra, 31200, Spain.
Iván
I
Méndez
NeuroEpigenetics Laboratory, Navarrabiomed- IdiSNA (Navarra Institute for Health Research), c/ Irunlarrea, 3, Pamplona, Navarra, 31008, Spain.|Hospital Psicogeriátrico Josefina Arregui, Alsasua, Navarra, 31800, Spain.
Carmen
C
Echávarri
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult; D016875:tau Proteins
C500984:CRTC1 protein, human; C054369:MAPT protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; D016875:tau Proteins
Alzheimer’s disease; CRTC1; DNA methylation; Epigenetics; Hippocampus