John C. Schimenti

Modeling of human MLH1 and MLH3 variants in mice reveals novel functions of MutLγ in meiotic DNA repair and the ovarian reserve

This study models human MLH1 and MLH3 variants in mice, revealing MutLγ's roles in meiotic DNA repair and ovarian reserve maintenance through multiple mechanisms.

Chronic replication stress-mediated genomic instability disrupts placenta development in mice

This study shows that replication stress from MCM2-7 mutations impairs placenta development in mice by reducing junctional zone proliferation and stemness, leading to poor embryo viability.

Embryonic Stem Cell-Specific Responses to DNA Replication Stress

This study investigates how mouse embryonic stem cells respond to DNA replication stress, finding they survive via ATR- and CHK1-dependent mechanisms but lack a strong G2/M checkpoint and repair DNA crosslinks in S phase.

Combinatorial organoid mutagenesis screen reveals gene constellations driving malignant transformation, pathology and chemosensitivity in high-grade serous ovarian carcinoma

This study uses combinatorial CRISPR mutagenesis in organoids to identify gene combinations driving malignant transformation, pathology, and chemosensitivity in high-grade serous ovarian carcinoma.

Integrative genome-scale analyses reveal post-transcriptional signatures of early human smallintestinal development in a directed differentiation organoid model

The paper identifies post-transcriptional regulators in early human small intestinal development using multi-omic analyses and presents a web tool for exploring miRNA regulation.

Sequencing Micronuclei Reveals the Landscape of Chromosomal Instability

The paper develops MN-seq to sequence DNA in micronuclei, revealing factors contributing to chromosomal instability and introducing scMN-seq for single-cell analysis.

In vivo versus in silico assessment of potentially pathogenic missense variants in human reproductive genes

The paper evaluates the functional impact of missense variants in human reproductive genes using mouse models and finds that many predicted pathogenic variants do not cause detectable phenotypes.

MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging

The paper identifies MLH1/3 variants in mice that cause reproductive defects, including subfertility and increased pregnancy loss due to meiotic abnormalities.

Prime Editing in Mice Reveals the Essentiality of a Single Base in Driving Tissue-Specific Gene Expression

This paper compares CRISPR-mediated HDR and PE2 systems in mice to show PE2's higher fidelity in editing a TFBS, leading to more effective tissue-specific gene inactivation.

Sexually Dimorphic DNA Damage Responses and Mutation Avoidance in the Mouse Germline

This study investigates DNA damage responses in mouse primordial germ cells, showing sex-specific differences in mutation avoidance and developmental outcomes after ionizing radiation exposure.

Variants in RABL2A causing male infertility and ciliopathy

The paper identifies two RABL2A variants causing male infertility and ciliopathies by combining in silico predictions, protein stability assays, and mouse modeling.

Single Cell Analysis Reveals Multi-faceted miR-375 Regulation of the Intestinal Crypt

This study identifies miR-375 as a key regulator of intestinal crypt homeostasis, showing its role in stem cell proliferation, tuft cell abundance, and resistance to infection and cancer.

Signaling to TRP53 and TAp63 from CHK1/CHK2 is responsible for elimination of most oocytes defective for either chromosome synapsis or recombination

The paper shows that CHK1/CHK2 signaling to TRP53/TAp63 eliminates oocytes with unrepaired meiotic DSBs or asynaptic chromosomes.

A predicted deleterious allele of the essential meiosis gene MND1, present in ~3% of East Asians, does not disrupt reproduction in mice.

The paper identifies a predicted deleterious SNP in the MND1 gene present in East Asians but shows it does not affect mouse fertility.

A segregating human allele of SPO11 modeled in mice disrupts timing and amounts of meiotic recombination, causing oligospermia and a decreased ovarian reserve.

The paper models a human SPO11 variant in mice, showing it disrupts meiotic recombination, leading to reduced sperm and oocytes and fertility issues.

Female-biased embryonic death from genomic instability-induced inflammation

The paper shows female mouse embryos are more susceptible to embryonic lethality from genomic instability-induced inflammation, which is mitigated by testosterone or anti-inflammatory drugs.

CDK2 kinase activity is a regulator of male germ cell fate

This study shows that CDK2 kinase activity regulates male germ cell fate by controlling the balance between stem cell renewal and differentiation, with loss of function leading to infertility.

A putative human infertility allele of the meiotic recombinase DMC1 does not affect fertility in mice

The paper creates a mouse model of a putative infertility allele, DMC1M200V, and finds it does not affect fertility in mice.

A Single Checkpoint Pathway Eliminates Mouse Oocytes With DNA Damage Or Chromosome Synapsis Failure

The paper shows that the CHK2-dependent checkpoint eliminates mouse oocytes with DNA damage or synapsis failure by detecting and removing those with unrepaired DSBs or unsynapsed chromosomes.

Mcmdc2, a minichromosome maintenance (MCM) paralog, is required for repair of meiotic DNA breaks and homolog pairing in mouse meiosis

This study shows that MCMDC2 is essential for meiotic DNA break repair and homolog pairing in mice, with phenotypes similar to MSH4/5 deficiency.