Cook, C. J. | Search bioRxiv

bioRxiv2023

Characterizing the extracellular matrix transcriptome of endometriosis

In recent years, the matrisome, a set of proteins that make up the extracellular matrix (ECM) or are closely involved in ECM behavior, has been shown to have great importance for characterizing and understanding disease pathogenesis and progression. The matrisome is especially critical for examining diseases characterized by extensive tissue remodeling. Endometriosis is characterized by the extrauterine growth of endometrial tissue, making it an ideal condition to study through the lens of matrisome gene expression. While large gene expression datasets have become more available, and gene dysregulation in endometriosis has been the target of several studies, the gene expression profile of the matrisome specifically in endometriosis has not been well characterized. In our study, we explored three Gene Expression Omnibus (GEO) DNA microarray datasets containing endometriosis and healthy samples of eutopic endometrium. We established that matrisome gene expression alone can stratify healthy and endometriosis samples and identified the matrisome genes and gene networks that hold inferential significance for the onset and progression of endometriosis. Furthermore, we found that menstrual cycle phase accounted for over a third of the variance of matrisome gene expression within the samples. Taken together, these findings may aid in developing future in vitro models of disease and identifying novel treatment strategies for this underserved patient population.

bioinformatics↗

bioRxiv2022

Characterizing the extracellular matrix transcriptome of cervical, endometrial, anduterine cancers

Increasingly, the matrisome, a set of proteins that form the core of the extracellular matrix (ECM) or are closely associated with it, has been demonstrated to play a key role in tumor progression. However, in the context of gynecological cancers, the matrisome has not been well characterized. A holistic, yet targeted, exploration of the tumor microenvironment is critical for better understanding the progression of gynecological cancers, identifying key biomarkers for cancer progression, establishing the role of gene expression in patient survival, and for assisting in the development of new targeted therapies. In this work, we explored the matrisome gene expression profiles of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), uterine corpus endometrial carcinoma (UCEC), and uterine carcinosarcoma (UCS) using publicly available RNA-seq data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) portal. We hypothesized that the matrisomal expression patterns of CESC, UCEC, and UCS would be highly distinct with respect to genes which are differentially expressed and hold inferential significance with respect to tumor progression, patient survival, or both. Through a combination of statistical and machine learning analysis techniques, we identified sets of genes and gene networks which characterized each of the gynecological cancer cohorts. Our findings demonstrate that the matrisome is critical for characterizing gynecological cancers and transcriptomic mechanisms of cancer progression and outcome. Furthermore, while the goal of pan-cancer transcriptional analyses is often to highlight the shared attributes of these cancer types, we demonstrate that they are highly distinct diseases which require separate analysis, modeling, and treatment approaches. In future studies, matrisome genes and gene ontology terms that were identified as critical for predicting patient survival or cancer stage can be evaluated as potential drug targets and incorporated into in vitro models of disease.

cancer biology↗

bioRxiv2021

Genetic influence on resting state networks in young male and female adults

Determining genetic versus environmental influences on the human brain is of crucial importance to understand the healthy brain as well as in a variety of disease and disorder states. Here we propose a unique, minimal assumption, approach to investigate genetic influence on the functional connectivity of the brain using 260 subjects" (65 monozygotic (MZ) and 65 dizygotic (DZ) healthy young adult twin pairs) resting state fMRI (rsfMRI) data from the Human Connectome Project (HCP). For any given resting state connection between twin pairs, the connection strengths across pairs were subtracted from each other in both directions. By applying the F-Test for equality of variances per connection, we found that there were a number of significant connections that demonstrated greater variance among dizygotic pairs in comparison to monozygotic pairs, implying these connections were under significant genetic influence. These population (DZ-MZ) results remained true irrespective of gender, with the caveat that certain connections were significant on a gender-specific basis. This is the first study to our knowledge to assess the heritability across young healthy adults both in general and specific to gender. Population Results & DiscussionAt the population level, there appears to be a posterior to anterior gradient of more to less genetic influence on brain connections and networks with visual > temporal, parietal > frontal. There was a high density of genetically-influenced functional connections predominantly involving posterior regions or networks of the brain: Visual Networks (VNs - primary visual, early visual, dorsal stream and ventral stream visual cortices, MT+ complex). These posterior regions of the brain with greater genetic influence are implicated for example in visual, perceptual, dorsal ("where") and ventral ("what") visuospatial processing streams (VNs). There was a low-density or paucity of genetically-influenced functional connections predominantly involving anterior regions or networks of the brain comprising Task Positive Networks (TPNs): FrontoParietal Networks (FPNs - dorsolateral prefrontal, orbital and polar frontal, midcingulate, insular and frontal opercular, superior and inferior parietal cortices); FrontoTemporal Networks (FTNs - inferior frontal, posterior opercular, early auditory, auditory association cortices); Sensorimotor Networks (SMNs - premotor, somatosensory, paralobular, and motor cortices); These anterior regions of the brain with lesser genetic influence are implicated in various TPN processes; for example in high-level cognitive and affective processes such as working memory, executive function, reasoning, attentional and impulse control, emotional judgement and decision making (FPNs); language and auditory processes (FTNs); action-planning and movement processes (SMN). There was a mix of high (posterior) and low (anterior) density of genetically influenced functional connections involving the extended Default Mode Network (eDMN). Specifically, there was a high density of genetically-influenced functional connections involving predominantly posterior-medial regions of eDMN - hippocampus and precuneus/posterior cingulate cortices; There was a low density of genetically influenced connections involving anterior regions (anterior cingulate and medial prefrontal) and lateral (inferior parietal, temporoparietooccipital) regions of the eDMN. The eDMN is involved in low-level cognitive and affective processes such as those involved in episodic memory retrieval, mental imagery, introspection, rumination, evaluation of self and others. These differences in genetic influence on posterior (more) vs. anterior (less) brain regions may have implications in terms of the environmental influence (e.g., education, school and work environment, family and home environment, social interaction with friends and peers, medications, nutrition, sports and physical exercise) on posterior (less) vs. anterior (more) portions of the brain during development and later in life. Gender-Specific Results & DiscussionAs noted at the population level, both males and females were under extensive genetic influence in terms of network interactions involving visual cortices. In addition, males were more genetically influenced in terms of network interactions involving auditory-language related cortices compared to females. This finding suggests that males may be more functionally "hard-wired" and females may be more environmentally influenced and shaped in terms of auditory-language systems than males. As noted at the population level, both males and females were under extensive genetic influence in terms of interactions involving the eDMN which is considered a central hub of the brain for various processes such as internal monitoring, rumination and evaluation of self and others, as noted previously. In addition, males also were more genetically influenced compared to females in terms of intranetwork and internetwork interactions of eDMN and other brain regions (occipital, temporal, parietal, and frontal regions) involved in various task-oriented processes and attending to and interacting with the environment which comprise part of the Task Positive Networks (TPNs). There were also nearly five times more genetically influenced functional connections in males (310) than females (64) suggesting that male brains are more genetically influenced, i.e. functionally "hard-wired", than females. This result suggests differences in genetic predisposition in males (more) vs. females (less) in terms of interplay of attending to task-oriented interactions with the environment (TPNs) vs. internal and external interactions with self and others (eDMN). This finding may also have implications in terms of brain plasticity differences in males (less) versus females (more) in terms of ability to react or adapt/maladapt to environmental influences (e.g. task completion demands, psychosocial stressors, positive and negative feedback, meditation, cognitive behavioral therapy, pharmacotherapy) and their overall malleability. These results reveal the similarities and differences of genetics and environmental influences on different connections, areas, and networks of the resting state functional brain in young healthy males and females with implications in development and later in life. This unique method can be applied in healthy as well as in patient populations to reveal the genetic and environmental influences on the brain. SignificanceThere were high vs. low genetic influences on posterior vs. anterior brain regions involved in low-level visuospatial processes vs. high-level cognitive processes such as reasoning and language respectively. This finding may have implications in terms of the brain to be environmentally influenced (e.g., school, work and home environment) during development and later in life. There were nearly five times more genetically influenced functional connections in males than females in brain regions involved in task-oriented interactions with environment vs. interactions with self and others. This finding may have implications in terms of brain plasticity differences in males (less) versus females (more) in terms of ability to adapt/maladapt to environmental influences (e.g. task completion demands, psychosocial stressors, various therapies) and their overall malleability. This is the first study to our knowledge to assess the heritability across young healthy adults both in general and specific to gender.

neuroscience↗