4.8 Article

Prenatal Cadmium Exposure Alters Proliferation in Mouse CD4+ T Cells via LncRNA Snhg7

期刊

FRONTIERS IN IMMUNOLOGY
卷 12, 期 -, 页码 -

出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.720635

关键词

long non-coding RNA; Snhg7; CD4(+) T cells; cadmium; GALNT7; miR-34a

资金

  1. National Institution of Environmental Health Sciences [ES023845]
  2. National Institutes of Health [S10OD016165, RRID : SCR_017738]
  3. Institutional Development Awards (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health [P30GM121322, P20GM103434]
  4. West Virginia IDeA-CTR (NIH/NIGMS) [2U54 GM104942-03]
  5. National Science Foundation [NSF/1920920, NSF/1761792]
  6. WV-INBRE [P20 GM103434]
  7. NIGMS [U54 GM-104942]
  8. [SCR_017738]

向作者/读者索取更多资源

Prenatal cadmium exposure alters the expression of lncRNAs during T cell activation, with the induction of lncSnhg7 being enhanced in T cells from Cd-exposed offspring leading to upregulation of GALNT7 protein and increased proliferation. Overexpression of miR-34a decreases GALNT7 expression, while knockdown of lncSnhg7 inhibits CD4(+) T cell proliferation.
ObjectivePrenatal cadmium (Cd) exposure leads to immunotoxic phenotypes in the offspring affecting coding and non-coding genes. Recent studies have shown that long non-coding RNAs (lncRNAs) are integral to T cell regulation. Here, we investigated the role of long non-coding RNA small nucleolar RNA host gene 7 (lncSnhg7) in T cell proliferation. MethodsRNA sequencing was used to analyze the expression of lncRNAs in splenic CD4(+) T cells with and without CD3/CD28 stimulation. Next, T cells isolated from offspring exposed to control or Cd water throughout mating and gestation were analyzed with and without stimulation with anti-CD3/CD28 beads. Quantitative qPCR and western blotting were used to detect RNA and protein levels of specific genes. Overexpression of a miR-34a mimic was achieved using nucleofection. Apoptosis was measured using flow cytometry and luminescence assays. Flow cytometry was also used to measure T cell proliferation in culture. Finally, lncSnhg7 was knocked down in splenic CD4(+) T cells with lentivirus to assess its effect on proliferation. ResultsWe identified 23 lncRNAs that were differentially expressed in stimulated versus unstimulated T cells, including lncSnhg7. LncSnhg7 and a downstream protein, GALNT7, are upregulated in T cells from offspring exposed to Cd during gestation. Overexpression of miR-34a, a regulator of lncSnhg7 and GALNT7, suppresses GALNT7 protein levels in primary T cells, but not in a mouse T lymphocyte cell line. The T cells isolated from Cd-exposed offspring exhibit increased proliferation after activation in vitro, but Treg suppression and CD4(+) T cell apoptosis are not affected by prenatal Cd exposure. Knockdown on lncSnhg7 inhibits proliferation of CD4(+) T cells. ConclusionPrenatal Cd exposure alters the expression of lncRNAs during T cell activation. The induction of lncSnhg7 is enhanced in splenic T cells from Cd offspring resulting in the upregulation of GALNT7 protein and increased proliferation following activation. miR-34a overexpression decreased GALNT7 expression and knockdown of lncSnhg7 inhibited proliferation suggesting that the lncSnhg7/miR-34a/GALNT7 is an important pathway in primary CD4(+) T cells. These data highlight the need to understand the consequences of environmental exposures on lncRNA functions in non-cancerous cells as well as the effects in utero.

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