Clarifying Mendelian vs non-Mendelian inheritance.

Gregor Mendel developed the principles of segregation and independent assortment in the mid-1800s based on his detailed analysis of several traits in pea plants. Those principles, now called Mendel's laws, in fact, explain the behavior of genes and alleles during meiosis and are now understood to underlie "Mendelian inheritance" of a wide range of traits and diseases across organisms. When asked to give examples of inheritance that do NOT follow Mendel's laws, in other words, examples of non-Mendelian inheritance, students sometimes list incomplete dominance, codominance, multiple alleles, sex-linked traits, and multigene traits and cite as their sources the Khan Academy, Wikipedia, and other online sites.

DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in FLC is its driver mutation, a conserved DNAJB1-PRKACA gene fusion that could be an ideal target neoantigen for immunotherapy. In this study, we aim to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) for use in cellular immunotherapies.

Fc multimers effectively treat murine models of multiple sclerosis.

Multiple Sclerosis (MS) is a chronic neurodegenerative disease with limited therapeutic options. Recombinant Fc multimers (rFc), designed to mirror many of the anti-inflammatory activities of Intravenous Immunoglobulin (IVIG), have been shown to effectively treat numerous immune-mediated diseases in rodents. In this study we used the experimental autoimmune encephalomyelitis (EAE) murine model of MS to test the efficacy of a rFc, M019, that consists of multimers of the Fc portion of IgG2, in inhibiting disease severity.

Complement component C1q is an immunological rheostat that regulates Fc:Fc[Formula: see text]R interactions.

Though binding sites for the complement factor C1q and the canonical fragment crystallizable (Fc) gamma receptors (Fc[Formula: see text]Rs) on immunoglobulin G (IgG) molecules overlap, how C1q decoration of immune complexes (ICs) influences their ability to engage Fc[Formula: see text]Rs remains unknown. In this report, we use recombinant human Fc multimers as stable IC mimics to show that C1q engagement of ICs directly and transiently inhibits their interactions with Fc[Formula: see text]RIII (CD16) on human natural killer (NK) cells. This inhibition occurs by C1q engagement alone as well as in concert with other serum factors.

Sperm-inherited H3K27me3 epialleles are transmitted transgenerationally in .

The transmission of chromatin states from parent cells to daughter cells preserves cell-specific transcriptional states and thus cell identity through cell division. The mechanism that underpins this process is not fully understood. The role that chromatin states serve in transmitting gene expression information across generations via sperm and oocytes is even less understood.

Maternal H3K36 and H3K27 HMTs protect germline development via regulation of the transcription factor LIN-15B.

Maternally synthesized products play critical roles in the development of offspring. A premier example is the H3K36 methyltransferase MES-4, which is essential for germline survival and development in offspring. How maternal MES-4 protects the germline is not well understood, but its role in H3K36 methylation hinted that it may regulate gene expression in primordial germ cells (PGCs).

DREAM interrupted: severing LIN-35-MuvB association in Caenorhabditis elegans impairs DREAM function but not its chromatin localization.

The mammalian pocket protein family, which includes the Retinoblastoma protein (pRb) and Rb-like pocket proteins p107 and p130, regulates entry into and exit from the cell cycle by repressing cell cycle gene expression. Although pRb plays a dominant role in mammalian systems, p107 and p130 are the ancestral pocket proteins. The Rb-like pocket proteins interact with the highly conserved 5-subunit MuvB complex and an E2F-DP transcription factor heterodimer, forming the DREAM (for Dp, Rb-like, E2F, and MuvB) complex.

A primer for generating and using transcriptome data and gene sets.

Transcriptomic approaches have provided a growing set of powerful tools with which to study genome-wide patterns of gene expression. Rapidly evolving technologies enable analysis of transcript abundance data from particular tissues and even single cells. This Primer discusses methods that can be used to collect and profile RNAs from specific tissues or cells, process and analyze high-throughput RNA-sequencing data, and define sets of genes that accurately represent a category, such as tissue-enriched or tissue-specific gene expression.

SET1/COMPASS Maintains Germline Identity by Preventing Transcriptional Deregulation Across Generations.

Chromatin regulators contribute to the maintenance of the germline transcriptional program. In the absence of SET-2, the homolog of the SET1/COMPASS H3 Lys4 (H3K4) methyltransferase, animals show transgenerational loss of germline identity, leading to sterility. To identify transcriptional signatures associated with progressive loss of fertility, we performed expression profiling of mutant germlines across generations.

An implementation project to expand access to self-administered depot medroxyprogesterone acetate (DMPA).

Objective: To describe the implementation and results of a proactive patient outreach project to offer self-administered, depot medroxyprogesterone (DMPA) subcutaneous (SC) to interested patients at a California safety-net clinic following expanded state Medicaid coverage.

Study Design: We contacted non-pregnant patients at an urban, safety-net hospital-based primary care clinic who had been prescribed DMPA intramuscular (IM) in the past year to gauge interest in self-administered DMPA-SC. Interested patients received a prescription for DMPA-SC and a telehealth appointment with a clinic provider to learn self-injection.

Engineering of Fc Multimers as a Protein Therapy for Autoimmune Disease.

The success of Intravenous Immunoglobulin in treating autoimmune and inflammatory processes such as immune thrombocytopenia purpura and Kawasaki disease has led to renewed interest in developing recombinant molecules capable of recapitulating these therapeutic effects. The anti-inflammatory properties of IVIG are, in part, due to the Fc region of the IgG molecule, which interacts with activating or inhibitory Fcγ receptors (FcγRs), the neonatal Fc Receptor, non-canonical FcRs expressed by immune cells and complement proteins. In most cases, Fc interactions with these cognate receptors are dependent upon avidity-avidity which naturally occurs when polyclonal antibodies recognize unique antigens on a given target.

Conditional Reprogramming for Patient-Derived Cancer Models and Next-Generation Living Biobanks.

Traditional cancer models including cell lines and animal models have limited applications in both basic and clinical cancer research. Genomics-based precision oncology only help 2-20% patients with solid cancer. Functional diagnostics and patient-derived cancer models are needed for precision cancer biology.

Repression of Germline Genes in Somatic Tissues by H3K9 Dimethylation of Their Promoters.

Repression of germline-promoting genes in somatic cells is critical for somatic development and function. To study how germline genes are repressed in somatic tissues, we analyzed key histone modifications in three synMuv B mutants, , , and -all of which display ectopic expression of germline genes in the soma. LIN-35 and LIN-37 are members of the conserved DREAM complex.

Sperm-inherited H3K27me3 impacts offspring transcription and development in C. elegans.

Paternal epigenetic inheritance is gaining attention for its growing medical relevance. However, the form in which paternal epigenetic information is transmitted to offspring and how it influences offspring development remain poorly understood. Here we show that in C.

NK cell expression of Tim-3: First impressions matter.

Given the heightened interest in manipulation of co-signaling cascades for cancer immunotherapy, we sought to determine how/whether tumors decorated with therapeutic monoclonal antibodies (mAbs) impact the expression of co-signaling molecules on human NK cells. Stimulation of NK cells with aggregated IgG1 resulted in the upregulation of HAVCR2 - the gene encoding T-cell immunoglobulin and mucin-containing domain (Tim)-3 - known to be involved in the induction of peripheral T cell tolerance. This upregulation of HAVCR2 was recapitulated at the protein level, following NK cell stimulation by either mAb opsonized tumors, recombinant human IgG1 Fc multimer, and/or non-Fc stimuli e.

Intratumor genetic heterogeneity in squamous cell carcinoma of the oral cavity.

Background: We sought to evaluate intratumor heterogeneity in squamous cell carcinoma of the oral cavity (OCC) and specifically determine the effect of physical separation and histologic differentiation within the same tumor.

Methods: We performed whole exome sequencing on five biopsy sites-two from well-differentiated, two from poorly differentiated regions, and one from normal parenchyma-from five primary OCC specimens.

Results: We found high levels of intratumor heterogeneity and, in four primary tumors, identified only 0 to 2 identical mutations in all subsites.

The evolving role of immuno-oncology for the treatment of head and neck cancer.

Monoclonal antibodies (mAbs) that target immune co-signaling pathways have the potential to enable immune mediated tumor eradication. While early adoption of these agents for the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN) has produced some astounding clinical successes, the majority of patients fail to respond to therapy. The purpose of this review is to first provide a broad overview of the immuno-oncology (I-O) landscape and to then focus on the current status of mAb-based I-O (mAb:I-O) for the treatment of SCCHN, with particular attention to the development of strategies for improving treatment responses.

A recombinant human IgG1 Fc multimer designed to mimic the active fraction of IVIG in autoimmunity.

The antiinflammatory effects of i.v. Ig (IVIG) in the treatment of autoimmune disease are due, in part, to the Fc fragments of Ig aggregates.

Caenorhabditis elegans sperm carry a histone-based epigenetic memory of both spermatogenesis and oogenesis.

Paternal contributions to epigenetic inheritance are not well understood. Paternal contributions via marked nucleosomes are particularly understudied, in part because sperm in some organisms replace the majority of nucleosome packaging with protamine packaging. Here we report that in Caenorhabditis elegans sperm, the genome is packaged in nucleosomes and carries a histone-based epigenetic memory of genes expressed during spermatogenesis, which unexpectedly include genes well known for their expression during oogenesis.

Distinct Roles of Two Histone Methyltransferases in Transmitting H3K36me3-Based Epigenetic Memory Across Generations in .

Epigenetic information contributes to proper gene expression and development, and can be transmitted not only through mitotic divisions but also from parents to progeny. We investigated the roles in epigenetic inheritance of MES-4 and MET-1, the two enzymes that methylate H3K36 (histone H3 Lys 36). Mass spectrometry analysis confirmed immunostaining results showing that both MES-4 and MET-1 catalyze H3K36me3.

A fully recombinant human IgG1 Fc multimer (GL-2045) inhibits complement-mediated cytotoxicity and induces iC3b.

GL-2045 is a recombinant human immunoglobulin G1 (IgG1)-based Fc multimer designed to recapitulate the anti-inflammatory activities of intravenous immunoglobulin (IVIG) on the innate and adaptive immune responses. We used functional in vitro studies to determine if GL-2045 could mimic the modulatory activity of IVIG on complement activation. GL-2045, at log-order lower concentrations than heat-aggregated IgG (HAGG) and IVIG, protected antibody-opsonized cells from complement-dependent cytotoxicity.

Loss of the Caenorhabditis elegans pocket protein LIN-35 reveals MuvB's innate function as the repressor of DREAM target genes.

The DREAM (Dp/Retinoblastoma(Rb)-like/E2F/MuvB) transcriptional repressor complex acts as a gatekeeper of the mammalian cell cycle by establishing and maintaining cellular quiescence. How DREAM's three functional components, the E2F-DP heterodimer, the Rb-like pocket protein, and the MuvB subcomplex, form and function at target gene promoters remains unknown. The current model invokes that the pocket protein links E2F-DP and MuvB and is essential for gene repression.