Diet-induced- and genetic-obesity differentially alters male germline histones

in Reproduction
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  • 1 Department of Neuroendocrinology, ICMR-National Institute for Research in Reproductive Health, Parel, Mumbai, India
  • | 2 National Institute of Nutrition Animal Facility, ICMR-National Institute of Nutrition, Hyderabad, India

Correspondence should be addressed to N H Balasinor; Email: balasinorn@nirrh.res.in
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Obesity, an established risk factor for male subfertility or infertility, is primarily due to genetic and environmental causes. Our earlier studies have shown differential effects of high-fat diet-induced- (DIO) and genetically inherited- (GIO) obesity on DNA methylation in male germline and its subsequent effect on fertility. Here, we hypothesized that the effects of DIO and GIO on histone modifications in male germline could also contribute to fertility defects. We observed that DIO affected both active (H3K4me3, H3ac, and H4ac) and repressive (H3K9me3 and H3K27me3) histone marks in testis and their cell types, whereas GIO solely altered acetylated histones. This correlated with the deregulation of histone-modifying enzymes in the testis of both obese groups. Further, we also observed a decrease in chromatin remodelers in the testis of the DIO group, which were increased in the GIO group. Besides, there was an increase in core histones and a decrease in histone marks along with protamine deficiency in spermatozoa of the DIO group, whereas only H3K4me3 levels were increased in spermatozoa of the GIO group. Moreover, we observed alterations in the expression and enrichment patterns of a few developmental genes harbored by the active histone mark in resorbed embryos and spermatozoa of DIO rats. Together these epigenetic defects in the male germline could alter sperm quality and cause fertility defects in these obese groups. Differential changes in two obese groups could also be attributed to differences in their pathophysiological variations. Our study highlights epigenetic differences between DIO and GIO in the male germline and their subsequent impact on male fertility.

Supplementary Materials

    • Supplementary Figure 1: Gating strategy for combined histone modifications and propidium iodide (PI) staining using flow cytometry. Testicular cells were labelled with antibody specific for various histone modifications prior to DNA staining with PI. For analysis, the testicular cells were gated A) according to their FSC and SSC parameters (P1 region) and B) then selected based on their PI content (P2 region). C) specific histone modification staining of the P2 cells i.e. P4 purple region and its isotypic control i.e. P3 blue region were shown as a dot plot. Analysis of cell cycle (D) is combined with analysis of specific histone modification (C) and is viewed as a dot plot (E). P5 and P11 represents elongated spermatid population; P6 and P12 represents elongating spermatid population; P7 and P13 represents round spermatid population; P8 and P14 represents 2N population; P9 and P15 represents S phase population and P10 and P16 represents 4N population.
    • Supplementary Figure 2: Representative dot plots for combined histone modifications (A) H3K4me3, (B) H3K9me3, (C) H3K27me3, (D) H3ac, and (E) H4ac and propidium iodide (PI) staining using flow cytometry in the testis of HFD group compared to CD group. P11 represents elongated spermatid population; P12 represents elongating spermatid population; P13 represents round spermatid population; P14 represents 2N population; P15 represents S phase population and P16 represents 4N population.
    • Supplementary Figure 3: Representative dot plots for combined histone modifications (A) H3K4me3, (B) H3K9me3, (C) H3K27me3, (D) H3ac, and (E) H4ac and propidium iodide (PI) staining using flow cytometry in the testis of WNIN/Ob group compared to CROb and LEAN groups respectively. P11 represents elongated spermatid population; P12 represents elongating spermatid population; P13 represents round spermatid population; P14 represents 2N population; P15 represents S phase population and P16 represents 4N population.
    • Supplementary Figure 4: Representative plots showing the gating strategy for histone modification/protamine specific antibody staining of spermatozoa using flow cytometry. A) Unstained sperm sample, B) Negative control sperm sample and C) histone modification/ protamine specific antibody stained sperm sample. Sperm cells were gated based on their FSC and SSC parameters (P1 region) and then DAPI positive sperm cells were selected (P2 region). From the DAPI positive sperm cell population (P2 region), specific histone modification/protamine (FITC) positive sperm population was selected and represented in the form of histogram (P4 region). P3 region represents the specific histone modification/ protamine (FITC) negative sperm population, P5 represents DAPI negative population and P6 represents the DAPI positive sperm population.
    • Supplementary Figure 5: Representative histograms of histone modifications/protamine levels in spermatozoa. A) H3K4me3, B) H3K9me3, C) H3K27me3, D) H3ac, E) H4ac, and F) Prm1, G) H3 and H) H4 protein levels. P3 region represents the specific histone modification/ protamine (FITC) negative sperm population and P4 represents histone modification/Prm1 positive sperm population.
    • Supplementary Figure 6: Optimization of the sonication conditions for rat sperm chromatin isolation. The chromatin was sonicated using the following settings: 25% amplitude, and 30sec ON, and 30sec OFF for 10, 16, 20, 30, and 40 cycles. The resulting chromatin was purified using GeneAll Expin CleanUp SV mini kit and loaded onto a 1% agarose gel. The optimal chromatin size (~500 bp) was obtained after 16 mins of sonication and was used for subsequent ChIP experiments. ‘L’ indicates the DNA ladder (range 100-1000 bp)
    • Supplementary Figure 7: Graphs representing enrichment obtained following ChIP with anti-H3K4me3 and H3K27me3 over IgG (mock) A) Igf2r, Igf2, Cdkn1c, Irx1, Mir17, and Mirlet7e genes at specific locations and B) represents the cross validation of Irx1 and Mir17 genes at the histones - H3K4me3 and H3K27me3 over IgG where they are not known to be enriched. n=6 per group. Results are expressed as mean ±S.E.M. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001.
    • Supplementary Figure 8: Melt curves for genes analyzed in testis and resorbed embryos by q-RT-PCR.
    • Supplementary Table 1. Category wise gene list with primer sequences and conditions used for qRT-PCR and the size of PCR products.
    • Supplementary Table 2. ChIP-qPCR primer sequences, product size and annealing temperature.
    • Supplementary Table 3. MIQE Checklist

 

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