Paternal Deficiency of Trim66 Causes Intrauterine Overgrowth in Mice

Core Concepts

Paternal deficiency of the chromatin-binding protein Trim66 causes viable intrauterine overgrowth in the offspring.

Abstract

The study investigates the biological function of the chromatin-binding protein TRIM66 in male germ cells and its impact on offspring development. Key findings:

TRIM66 is specifically expressed in post-meiotic round and elongated spermatids, but not in oocytes or early embryos.
TRIM66's PHD-Bromo domain binds to the histone H3 N-terminus when lysine 4 is unmethylated.
Disruption of Trim66 in male germ cells, but not females, leads to offspring that are significantly heavier at birth compared to wild-type controls.
The sperm produced by Trim66-deficient males exhibit normal parameters, including count, motility, and fertilization capacity.
Transcriptome analysis of Trim66-deficient round spermatids reveals upregulation of genes involved in histone acetylation and H3K4 methylation, but the H3K4me3 profile in mature sperm is minimally affected.
The mechanism by which paternal Trim66 deficiency causes intrauterine overgrowth remains unclear, but may involve altered mRNA or protein content in the sperm that influences early embryonic development.

Stats

The average weight of pups sired by homozygous Trim66gfp/gfp males was 1.40 g ± 0.187 g, while the weight of pups from wild-type controls was 1.31 g ± 0.176 g (p=6.11x10-6).
The average weight of pups sired by homozygous Trim66phd/phd males was 1.38 g ± 0.193 g, compared to 1.34 g ± 0.205 g from wild-type fathers (p=2.87 x 10-2).

Quotes

"Pups sired by homozygous Trim66gfp/gfp males were on average 6.8% heavier than wild type at birth."
"The overweight phenotype persisted until weaning, albeit with a lower statistical significance (p=0.0146, two-sided t-test)."
"Besides being overweight at birth, pups sired by Trim66-deficient males appeared healthy, with no other obvious abnormalities."

Key Insights Distilled From

Trim66’s paternal deficiency causes intrauterine overgrowth

by Mielnicka,M.... at www.biorxiv.org 02-14-2024

https://www.biorxiv.org/content/10.1101/2024.02.12.579976v1

Deeper Inquiries

What are the potential mechanisms by which paternal Trim66 deficiency could influence fetal growth, beyond the observed changes in histone modifications and gene expression in spermatids?

Paternal Trim66 deficiency could influence fetal growth through various mechanisms beyond the observed changes in histone modifications and gene expression in spermatids. One potential mechanism could involve alterations in the epigenetic landscape of the sperm, such as changes in DNA methylation patterns or non-coding RNA content. These epigenetic modifications in the sperm could impact early embryonic development and gene expression in the offspring, leading to changes in growth and development.
Another possible mechanism could be related to the transmission of extracellular vesicles or other factors in the seminal fluid that carry information from the father to the developing embryo. These factors could influence fetal growth and development through signaling pathways or regulatory mechanisms that affect gene expression and cellular processes in the developing embryo.
Furthermore, the paternal effect of Trim66 on fetal growth could also involve interactions with the maternal environment during pregnancy. The altered sperm content or epigenetic modifications resulting from Trim66 deficiency may interact with maternal factors or signaling pathways, leading to changes in nutrient availability, hormone levels, or other factors that impact fetal growth and development.

How might the paternal effect of Trim66 on intrauterine growth be relevant to human health and metabolism, given the high evolutionary conservation of this gene?

The paternal effect of Trim66 on intrauterine growth could be highly relevant to human health and metabolism due to the high evolutionary conservation of this gene. Trim66 has been implicated in various biological processes, including gene regulation, chromatin remodeling, and spermatogenesis, which are essential for reproductive health and offspring development.
In humans, alterations in Trim66 function or expression could potentially impact fertility, reproductive outcomes, and offspring health. The observed paternal effect of Trim66 deficiency on intrauterine overgrowth in mice suggests that similar mechanisms may exist in humans, leading to potential implications for fetal growth and development.
Furthermore, the association of TRIM66 with metabolic traits in genome-wide association studies (GWAS) underscores its potential relevance to human health and metabolism. The influence of Trim66 on intrauterine growth could have long-term consequences for metabolic health and disease risk in offspring, highlighting the importance of understanding the molecular mechanisms underlying this paternal effect.

Could the altered mRNA or protein content in Trim66-deficient sperm that influences early embryonic development be identified through more comprehensive omic analyses?

Identifying the altered mRNA or protein content in Trim66-deficient sperm that influences early embryonic development could be achieved through more comprehensive omic analyses. Techniques such as RNA sequencing, proteomics, and metabolomics could be employed to profile the transcriptome, proteome, and metabolome of Trim66-deficient sperm compared to wild-type sperm.
By conducting these omic analyses, researchers could identify specific genes, proteins, or metabolites that are dysregulated in Trim66-deficient sperm and may play a role in influencing early embryonic development. These comprehensive analyses could provide insights into the molecular pathways and mechanisms through which Trim66 deficiency impacts sperm content and subsequent embryonic growth.
Moreover, integrating multiple omic datasets and performing systems biology analyses could help uncover complex interactions and regulatory networks involved in the paternal effect of Trim66 on early embryonic development. By combining different omic approaches, researchers can gain a holistic understanding of the molecular changes in Trim66-deficient sperm and their effects on offspring health and development.