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1.
bioRxiv ; 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38464133

ABSTRACT

Genetic variants can alter the profile of heritable molecules such as small RNAs in sperm and oocytes, and in this manner ancestral genetic variants can have a significant effect on offspring phenotypes even if they are not themselves inherited. Here we show that wild type female mice descended from ancestors with a mutation in the mammalian germ cell gene Khdc3 have hepatic metabolic defects that persist over multiple generations. We find that genetically wild type females descended from Khdc3 mutants have transcriptional dysregulation of critical hepatic metabolic genes, which persist over multiple generations and pass through both female and male lineages. This was associated with dysregulation of hepatically-metabolized molecules in the blood of these wild type mice with mutational ancestry. The oocytes of Khdc3-null females, as well as their wild type descendants, had dysregulation of multiple small RNAs, suggesting that these epigenetic changes in the gametes transmit the phenotype between generations. Our results demonstrate that ancestral mutation in Khdc3 can produce transgenerational inherited phenotypes, potentially indefinitely.

2.
Am J Kidney Dis ; 83(6): 829-833, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38211685

ABSTRACT

The etiologies of newborn deaths in neonatal intensive care units usually remain unknown, even after genetic testing. Whole-genome sequencing, combined with artificial intelligence-based methods for predicting the effects of non-coding variants, provide an avenue for resolving these deaths. Using one such method, SpliceAI, we identified a maternally inherited deep intronic PKHD1 splice variant (chr6:52030169T>C), in trans with a pathogenic missense variant (p.Thr36Met), in a newborn who died of autosomal recessive polycystic kidney disease at age 2 days. We validated the deep intronic variant's impact in maternal urine-derived cells expressing PKHD1. Reverse transcription polymerase chain reaction followed by Sanger sequencing showed that the variant causes inclusion of 147bp of the canonical intron between exons 29 and 30 of PKHD1 into the mRNA, including a premature stop codon. Allele-specific expression analysis at a heterozygous site in the mother showed that the mutant allele completely suppresses canonical splicing. In an unrelated healthy control, there was no evidence of transcripts including the novel splice junction. We returned a diagnostic report to the parents, who underwent in vitro embryo selection.


Subject(s)
Introns , Polycystic Kidney, Autosomal Recessive , Receptors, Cell Surface , Humans , Infant, Newborn , Male , Introns/genetics , Mutation, Missense , Polycystic Kidney, Autosomal Recessive/genetics , Polycystic Kidney, Autosomal Recessive/diagnosis , Receptors, Cell Surface/genetics
4.
Biol Reprod ; 105(3): 747-760, 2021 09 14.
Article in English | MEDLINE | ID: mdl-34159361

ABSTRACT

It is well established that environmental exposures can modify the profile of heritable factors in an individual's germ cells, ultimately affecting the inheritance of phenotypes in descendants. Similar to exposures, an ancestor's genotype can also affect the inheritance of phenotypes across generations, sometimes in offspring who do not inherit the genetic aberration. This can occur via a variety of prenatal, in utero, or postnatal mechanisms. In this review, we discuss the evidence for this process in mammals, with a focus on examples that are potentially mediated through the germline, while also considering alternate routes of inheritance. Noninherited ancestral genotypes may influence descendant's disease risk to a much greater extent than currently appreciated, and focused evaluation of this phenomenon may reveal novel mechanisms of inheritance.


Subject(s)
Epigenesis, Genetic , Genotype , Germ Cells/metabolism , Inheritance Patterns , Phenotype , Animals , Humans , Mice , Rats
5.
Clin Epigenetics ; 12(1): 136, 2020 09 11.
Article in English | MEDLINE | ID: mdl-32917273

ABSTRACT

It is becoming increasingly apparent that certain phenotypes are inherited across generations independent of the information contained in the DNA sequence, by factors in germ cells that remain largely uncharacterized. As evidence for germline non-genetic inheritance of phenotypes and diseases continues to grow in model organisms, there are fewer reports of this phenomenon in humans, due to a variety of complications in evaluating this mechanism of inheritance in humans. This review summarizes the evidence for germline-based non-genetic inheritance in humans, as well as the significant challenges and important caveats that must be considered when evaluating this process in human populations. Most reports of this process evaluate the association of a lifetime exposure in ancestors with changes in DNA methylation or small RNA expression in germ cells, as well as the association between ancestral experiences and the inheritance of a phenotype in descendants, down to great-grandchildren in some cases. Collectively, these studies provide evidence that phenotypes can be inherited in a DNA-independent manner; the extent to which this process contributes to disease development, as well as the cellular and molecular regulation of this process, remain largely undefined.


Subject(s)
DNA Methylation/genetics , Disease/genetics , Epigenomics/methods , Germ Cells/metabolism , Adolescent , Animals , Child , Female , Humans , Male , Mice , Middle Aged , Models, Animal , Phenotype , Smoking/genetics , Spermatozoa/metabolism , Thyroid Hormones/genetics , Wills
6.
Front Immunol ; 9: 1482, 2018.
Article in English | MEDLINE | ID: mdl-30022979

ABSTRACT

Peripheral T lymphocytes share many functional properties with hematopoietic stem cells (HSCs), including long-term maintenance, quiescence, and latent proliferative potential. In addition, peripheral T cells retain the capacity for further differentiation into a variety of subsets, much like HSCs. While the similarities between T cells and HSC have long been hypothesized, the potential common genetic regulation of HSCs and T cells has not been widely explored. We have studied the T cell-intrinsic role of Zfx, a transcription factor specifically required for HSC maintenance. We report that T cell-specific deletion of Zfx caused age-dependent depletion of naïve peripheral T cells. Zfx-deficient T cells also failed to undergo homeostatic proliferation in a lymphopenic environment, and showed impaired antigen-specific expansion and memory response. In addition, the invariant natural killer T cell compartment was severely reduced. RNA-Seq analysis revealed that the most dysregulated genes in Zfx-deficient T cells were similar to those observed in Zfx-deficient HSC and B cells. These studies identify Zfx as an important regulator of peripheral T cell maintenance and expansion and highlight the common molecular basis of HSC and lymphocyte homeostasis.

7.
Cell Rep ; 6(3): 528-40, 2014 Feb 13.
Article in English | MEDLINE | ID: mdl-24485662

ABSTRACT

Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) originate from different lineages through distinct oncogenic events such as MLL fusions and Notch signaling, respectively. We found that Zfx, a transcription factor that controls hematopoietic stem cell self-renewal, controls the initiation and maintenance of AML caused by MLL-AF9 fusion and of T-ALL caused by Notch1 activation. In both leukemia types, Zfx prevents differentiation and activates gene sets characteristic of immature cells of the respective lineages. In addition, endogenous Zfx contributes to gene induction and transformation by Myc overexpression in myeloid progenitors. Key Zfx target genes include the mitochondrial enzymes Ptpmt1 and Idh2, whose overexpression partially rescues the propagation of Zfx-deficient AML. These results show that distinct leukemia types maintain their undifferentiated phenotype and self-renewal by exploiting a common stem-cell-related genetic regulator.


Subject(s)
Cell Differentiation , Kruppel-Like Transcription Factors/metabolism , Leukemia, Myeloid, Acute/pathology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Animals , Cell Line, Tumor , Cell Proliferation , Cell Transformation, Neoplastic/pathology , Clone Cells , Gene Expression Regulation, Leukemic , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , Kruppel-Like Transcription Factors/genetics , Leukemia, Myeloid, Acute/genetics , Mice , Mitochondria/enzymology , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Phenotype , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Proto-Oncogene Proteins c-myc/metabolism , Receptors, Notch/metabolism
8.
Blood ; 113(23): 5857-67, 2009 Jun 04.
Article in English | MEDLINE | ID: mdl-19329779

ABSTRACT

The development, homeostasis, and function of B lymphocytes involve multiple rounds of B-cell receptor (BCR)-controlled proliferation and prolonged maintenance. We analyzed the role of transcription factor Zfx, a recently identified regulator of hematopoietic stem cell maintenance, in B-cell development and homeostasis. Panhematopoietic or B cell-specific deletion of Zfx in the bone marrow blocked B-cell development at the pre-BCR selection checkpoint. Zfx deficiency in peripheral B cells caused accelerated B-cell turnover, depletion of mature recirculating B cells, and delayed T-dependent antibody responses. In addition, the numbers and function of B-1 cell lineage were reduced. Zfx-deficient B cells showed normal proximal BCR signaling, but impaired BCR-induced proliferation and survival in vitro. This was accompanied by aberrantly enhanced and prolonged integrated stress response and by delayed induction of cyclin D2 and Bcl-xL proteins. Thus, Zfx restrains the stress response and couples antigen receptor signaling to cell expansion and maintenance during B-cell development and peripheral homeostasis. These results identify a novel transcriptional regulator of the B-cell lineage and highlight the common genetic control of stem cell maintenance and lymphocyte homeostasis.


Subject(s)
B-Lymphocytes/cytology , B-Lymphocytes/immunology , Kruppel-Like Transcription Factors/metabolism , Receptors, Antigen, B-Cell/immunology , Animals , B-Lymphocytes/metabolism , Cell Differentiation/immunology , Cell Proliferation , Cell Survival/immunology , Homeostasis/immunology , Kruppel-Like Transcription Factors/deficiency , Kruppel-Like Transcription Factors/genetics , Mice , Mice, Knockout , T-Lymphocytes/immunology
9.
J Exp Med ; 204(7): 1653-64, 2007 Jul 09.
Article in English | MEDLINE | ID: mdl-17591855

ABSTRACT

Signaling through Notch receptors and their transcriptional effector RBP-J is essential for lymphocyte development and function, whereas its role in other immune cell types is unclear. We tested the function of the canonical Notch-RBP-J pathway in dendritic cell (DC) development and maintenance in vivo. Genetic inactivation of RBP-J in the bone marrow did not preclude DC lineage commitment but caused the reduction of splenic DC fraction. The inactivation of RBP-J in DCs using a novel DC-specific deleter strain caused selective loss of the splenic CD8(-) DC subset and reduced the frequency of cytokine-secreting CD8(-) DCs after challenge with Toll-like receptor ligands. In contrast, other splenic DC subsets and DCs in the lymph nodes and tissues were unaffected. The RBP-J-deficient splenic CD8(-) DCs were depleted at the postprogenitor stage, exhibited increased apoptosis, and lost the expression of the Notch target gene Deltex1. In the spleen, CD8(-) DCs were found adjacent to cells expressing the Notch ligand Delta-like 1 in the marginal zone (MZ). Thus, canonical Notch-RBP-J signaling controls the maintenance of CD8(-) DCs in the splenic MZ, revealing an unexpected role of the Notch pathway in the innate immune system.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Immunoglobulin J Recombination Signal Sequence-Binding Protein/physiology , Spleen/immunology , Animals , CD11c Antigen/genetics , Dendritic Cells/drug effects , Flow Cytometry , Homeostasis , Immunoglobulin J Recombination Signal Sequence-Binding Protein/deficiency , Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics , Integrases/genetics , Lipopolysaccharides/pharmacology , Mice , Mice, Transgenic , Polymerase Chain Reaction , Receptors, Notch/physiology , Signal Transduction , Toll-Like Receptors/physiology
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