Cell line differences in replication timing of human glutamate receptor genes and other large genes associated with neural disease

<div><p>There is considerable current interest in the function of epigenetic mechanisms in neuroplasticity with regard to learning and memory formation and to a range of neural diseases. Previously, we described replication timing on human chromosome 21q in the THP-1 human cell line (2n = 46, XY) and showed that several genes associated with neural diseases, such as the neuronal glutamate receptor subunit GluR-5 (<i>GRIK1</i>) and amyloid precursor protein (<i>APP</i>), were located in regions where replication timing transitioned from early to late S phase. Here, we compared replication timing of all known human glutamate receptor genes (26 genes in total) and <i>APP</i> in 6 different human cell lines including human neuron-related cell lines. Replication timings were obtained by integrating our previously reported data with new data generated here and information from the online database ReplicationDomain. We found that many of the glutamate receptor genes were clearly located in replication timing transition zones in neural precursor cells, but this relationship was less clear in embryonic stem cells before neural differentiation; in the latter, the genes were often located in later replication timing zones that displayed DNA hypermethylation. Analysis of selected large glutamate receptor genes (>200 kb), and of <i>APP</i>, showed that their precise replication timing patterns differed among the cell lines. We propose that the transition zones of DNA replication timing are altered by epigenetic mechanisms, and that these changes may affect the neuroplasticity that is important to memory and learning, and may also have a role in the development of neural diseases.</p></div

Additional file 1 of Pure somatic pathogenic variation profiles for patients with serrated polyposis syndrome: a case series

Additional file 1: Table S1. DNA variant profile (Case #1)

Additional file 4 of Pure somatic pathogenic variation profiles for patients with serrated polyposis syndrome: a case series

Additional file 4: Table S4. Mutational signature of the single base substitution

Associations between final height and cardiometabolic outcomes in young adults with VLBW in the primary and extended analyses.

<p>*Associations were adjusted for sex, body weight, family history of diabetes, and SGA/AGA.</p>†<p>Associations were adjusted for sex, body weight, family history of diabetes, SGA/AGA, target height, and age at puberty onset.</p>‡<p>Measured during 75-g oral glucose tolerance tests.</p>§<p>eGFR = 194×Cre^−1.094× Age^−0.287 (×0.739 for females).</p><p>AGA, appropriate for gestational age; CI, confidence interval; eGFR, estimated glomerular filtration rate; fT4, free T4; SGA, small for gestational age; TSH, thyroid stimulating hormone.</p><p>Associations between final height and cardiometabolic outcomes in young adults with VLBW in the primary and extended analyses.</p

Predictive factors for the development of CVD in patients with IPF, according to univariate Cox proportional hazards analysis.

<p>CVD, collagen vascular disease; IPF, idiopathic pulmonary fibrosis; CI, confidence interval; SP-D, surfactant protein-D; FVC, forced vital capacity; BAL, bronchoalveolar lavage; HRCT, high-resolution computed tomography; GGO, ground-glass opacity.</p><p>*one or more positive systemic symptoms in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094775#pone-0094775-t002" target="_blank">Table 2</a>.</p><p>**one or more positive autoantibodies in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094775#pone-0094775-t003" target="_blank">Table 3</a>.</p

Treatment and outcome throughout the course of the patients who developed CVD and those with IPF.

<p>CVD, collagen vascular disease; IPF, idiopathic pulmonary fibrosis; CVD-IP, interstitial pneumonia associated with collagen vascular disease; ISA, immune suppressive agents; n. s., not significant.</p><p>*Pirfenidone (n = 14), N-acetylcysteine (NAC) (n = 5), intravenous immunoglobulin (IVIG) (n = 2), Pirfenidone+NAC (n = 1), Pirfenidone+IVIG (n = 1).</p

Survival curves for the patients who developed CVD and those with IPF.

<p>Patients who developed CVD had a significantly better survival rate than those with IPF (log-rank, <i>P</i> = 0.0433). IPF, idiopathic pulmonary fibrosis; CVD-IP, interstitial pneumonia associated with collagen vascular diseaseG.</p

HRCT and pathological findings in the patients who developed CVD and in those with IPF at the time of initial diagnosis.

<p>HRCT, high-resolution computed tomography; CVD, connective vascular disease; IPF, idiopathic pulmonary fibrosis; CVD-IP, interstitial pneumonia associated with collagen vascular disease; GGO, ground-glass opacity; n. s., not significant.</p><p>*scoring of the severity: absent 0, mild 1, moderate 2 and marked 3.</p

Parental height, target height, and age at puberty onset of subjects with VLBW who were included in the extended analyses.

<p>Data are expressed as the mean (SD) or <i>n</i> (%).</p><p>*<i>P</i> values are shown for the comparison between males and females.</p>†<p>Below the target height and <10th percentile.</p><p>Parental height, target height, and age at puberty onset of subjects with VLBW who were included in the extended analyses.</p

Systemic findings and autoantibodies in the patients who developed CVD and in those with IPF at the time of initial diagnosis.

<p>CVD, connective vascular disease; IPF, idiopathic pulmonary fibrosis; CVD-IP, interstitial pneumonia associated with collagen vascular disease; MPO-ANCA, myeloperoxidase antineutrophil cytoplasmic antibody; PR3-ANCA, proteinase 3-antineutrophil cytoplasmic antibody; n. s., not significant.</p