Marcela Preininger

University of California, Berkeley | UCB · Department of Molecular & Cell Biology

We describe a novel approach to capturing the covariance structure of peripheral blood gene expression that relies on the identification of highly conserved Axes of variation. Starting with a comparison of microarray transcriptome profiles for a new dataset of 189 healthy adult participants in the Emory-Georgia Tech Center for Health Discovery and...

β-blockers are unsuccessful in eliminating stress-induced ventricular arrhythmias in approximately 25% of patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from these patients have potential for investigating the phenomenon, but it remains unknown wh...

Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early a...

Blood-brain barrier dysfunction (BBBD) and accumulation of senescent astrocytes occur during brain aging and contribute to neuroinflammation and disease. Here, we explored the relationship between these two age-related events, hypothesizing that chronic hippocampal exposure to the blood-borne protein serum albumin could induce stress-induced premat...

As the most abundant cell types in the brain, astrocytes form a tissue-wide signaling network that is responsible for maintaining brain homeostasis and regulating various brain activities. Here, we review some of the essential functions that astrocytes perform in supporting neurons, modulating the immune response, and regulating and maintaining the...

How to cite this article: Muroy SE, Timblin GA, Preininger MK, Cedillo P, Saijo K. Phf15-a novel transcriptional repressor regulating inflammation in mouse microglia cell line. Neuroimmunol Neuroinflammation 2020;7:166-82. http://dx. Abstract Aim: Excessive microglial inflammation has emerged as a key player in mediating the effects of aging and ne...

Aim: Excessive microglial inflammation has emerged as a key player in mediating the effects of aging and neurodegeneration on brain dysfunction. Thus, there is great interest in discovering transcriptional repressors that can control this process. We aimed to examine whether Phf15, one of the top differentially expressed genes in microglia during a...

Immature phenotypes of cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) limit the utility of these cells in clinical application and basic research. During cardiac development, postnatal cardiomyocytes experience high oxygen tension along with a concomitant downregulation of hypoxia-inducible factor 1α (HIF-1α), leading...

Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early a...

Rationale: Recruitment of neutrophils to the airways, and their pathological conditioning therein, drive tissue damage and coincide with the loss of lung function in patients with cystic fibrosis (CF). So far, these key processes have not been adequately recapitulated in models, hampering drug development. Here, we hypothesized that the migration...

Document S1. Supplemental Experimental Procedures, Figures S1–S5, and Tables S1 and S2

Understanding molecules involved in differentiation of human pluripotent stem cells (hPSCs) into cardiomyocytes and endothelial cells is important in advancing hPSCs for cell therapy and drug testing. Here, we report that LGR5, a leucine-rich repeat-containing G-protein-coupled receptor, plays a critical role in hPSC differentiation into cardiomyoc...

In recent years, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have emerged as a vital cell source for in vitro modeling of genetic cardiovascular disorders, drug screening, and in vivo cardiac regeneration research. Looking forward, the ability to efficiently cryopreserve hPSC-CMs without compromising their normal biochemical and p...

Efficient generation of cardiomyocytes from human pluripotent stem cells is critical for their regenerative applications. Microgravity and 3D culture can profoundly modulate cell proliferation and survival. Here, we engineered microscale progenitor cardiac spheres from human pluripotent stem cells and exposed the spheres to simulated microgravity u...

Background: The autosomal dominant form of CPVT is linked to mutations in the gene encoding cardiac ryanodine receptor 2 (RyR2), an ion channel that regulates the coordinated release of Ca2+ from the sarcoplasmic reticulum (SR) to the cytosol during systole. RyR2 defects disturb channel gating, leading to aberrant Ca2+ release from the SR during di...

Background: Three-dimensional (3D) cardiac aggregates have the potential to improve efficient cardiac differentiation, cell growth, maturation and enrichment. Microgravity (MG) has profound effect on cell proliferation and cell survival. Therefore, we propose to study the effect of combining 3D tissue engineering and MG on proliferation, survival,...

Cystic Fibrosis (CF) lung disease is characterized by the massive recruitment of neutrophils (PMNs) into the bronchiolar lumen. Extracellular neutrophil elastase (NE) that is released from PMN primary granules, is a strong predictor of lung function and survival in CF patients. However, the process by which CF airway PMNs exocytose HNE is not well...

Bacteria colonize cystic fibrosis (CF) airways, and although T cells with appropriate Ag specificity are present in draining lymph nodes, they are conspicuously absent from the lumen. To account for this absence, we hypothesized that polymorphonuclear neutrophils (PMNs), recruited massively into the CF airway lumen and actively exocytosing primary...

Cardiomyocytes derived from human pluripotent stem cells (hPSCs) are a promising cell source for regenerative medicine, disease modeling, and drug discovery, all of which require enriched cardiomyocytes, ideally ones with mature phenotypes. However, current methods are typically performed in 2D environments that produce immature cardiomyocytes with...

Gene expression variation provides a read-out of both genetic and environmental influences on gene activity. Geographical, genomic and sociogenomic studies have highlighted how life circumstances of an individual modify the expression of hundreds and in some cases thousands of genes in a coordinated manner. This review places such results in the co...

List of covariates and Axis scores for five studies. Each sheet shows the individual identifier and coariates including Age, BMI, Percent Body Fat, Gender, Ethnicity, Location, and 8 types of cell count for the CHDWB; Location, Gender, Ethnicity and Age for Morocco (13); Gender, Age and BMI for Brisbane Red Cross (14); Study ID and PC1 for the TB s...

ToppFun gene ontology analysis of each of the 9 Axes. The top 500 genes listed in Dataset S1 were entered into ToppFun [19] on November 27, 2012. This sheet reports the major independent enrichments scores for each axis with respect to Gene Ontology classes (GO), Human or Mouse Phenotypes (HP or MP), Transcription Factor or miRNA binding sites, and...

Axis scores based on 5, 10, 20 or up to 250 BIT. The two spreadsheets show the PC1 scores based on the 5, 10, 20 or up to 250 most strongly associated probes listed in Dataset S1, for each axis. Within an axis, all four scores are highly correlated. (XLSX)

(A) Scatterplot of Eigenvalues for each of 14,343 transcripts on PC1 in the CHDWB and Morocco studies. While there is a strong correlation between the loadings for 90% of the transcripts, 10% all have higher values in the CHDWB study. This PC is highly correlated with Axis 4. (B) Lack of orthogonality of PC across studies. Each of PC2 through 5 in...

Blood Informative Axis scores. (A) Each plot shows the PC1 loadings of the 10 Bit transcripts in the CHDWB study on the right, and the individual PC1 and PC2 scores on the left. The same result for a typical random set of 10 probes is included as well. Panel J shows a histogram of the percent variance explained by PC1 for 100 random sets of 10 tran...

Cell counts correlate with specific Axes, but do not explain the axes. (A) T-lymphocyte count is positively correlated with Axis 1, but in part due to high scores of individuals with large T-cell counts. (B) Neutrophil counts are correlated with Axis 5, explaining 34% of the variance. Red females, blue males. (C) However, removing the effect of cel...

Replication of the association of BMI with Axis 2 in the Brisbane Red Cross study. Panels A and B show that BIT 2 correlates with both BMI and %BF in Atlanta CHDWB (%BF differs significantly between men and women). The same association is observed in Brisbane (C), where %BF data was not gathered. The volcano plots of significance (NLP, negative log...

Percent variance explained by PC1 for the entire set of probes annotated to the Chaussabel module genes (PVE_CHD and PVE_MOR refer to CHDWB Atlanta, and Morocco studies respectively), also showing the number of probes and genes, the Axis each module associates with, and the average for each measure. The bottom rows show the same values for the 175...

Independent evidence that the first 7 Axes are the major axes of covariance. For any set of covarying transcripts, some individuals will be expected to have low values of expression for multiple transcripts in the set, and these will be enriched in the low-expression transcripts of that individual. We thus reasoned that clustering of the variance c...

The covariance of BIT Axes is somewhat study-specific. Panels A and D show the correlation between the BIT Axis scores (namely, PC1 for the 10 probes as shown in Figure S2) for all individuals in CHDWB and Morocco respectively. Panels B and C (or E and F) then show a typical result of splitting each study into two halves, recomputing the Axis score...

Similarity of correlation structure among Axis scores (PC1 for each of the 10 BIT for each axis) across 6 independent whole blood datasets. In each of the Atlanta CHDWB, Morocco, Brisbane Red Cross (our studies), Celiac Disease, Tuberculosis, and Finland (DILGOM) (performed by others), Axes 1 and 3, and Axes 5 and 7, are to some extent positively c...

Heritability and differentiation of LCL and Peripheral Blood (PB) in the Brisbane twin study (18). PC1 scores for the 10 BIT per axis were computed for each dataset and are provided in Dataset S2. The percent variation of these BIT explained by PC1 is indicated in panel A, along with the significance (P-value) of the correlation between individual...

Correlation of Overall transcriptome PCA with Meta-Modules PC1 in Atlanta and Morocco. The values are the correlation coefficients between the first Principal Component for each of the indicated Meta-Modules and for Axis 6, and the first 5 Principal Components (Prin1-5) of the entire gene expression dataset for both the CHDWB Atlanta, and Morocco,...

List of genes associated with each of the 9 axes in both Atlanta and Morocco. The 9 sets of columns show the Illumina Probe identifier, the Gene name, and the negative logarithm of the p-value (NLP) for the association of the transcript with the axis score (PC1) in the multiple regression with all 9 axes in Atlanta (NLP_ATL) and Morocco (NLP_MOR)....

List of Blood Informative Transcripts including the Probe ID for the Illumina Human_HT12 bead chips. (DOCX)

Percent variance explained by PC1 for the 10 Blood Informative Transcripts for each Axis, in each of the 7 studies, showing high replication of their co-regulation. (DOCX)

List of 9 studies referred to in the paper, showing the Location of the population, number of samples, source of blood RNA, GEO or ArrayExpress accession number, and reference in this paper (CHDWB is reported for the first time). (DOCX)