1. Fundamental Primacy of the Epigenomic Effects
1.1. Layers of Epigenomic Regulation
1.2. Epigenomic Functions
This implies that the epigenomic state is central and pivotal to the control of cancer, cell development and aging, which are the three principal themes of the present discussion.
2. Epigenomic Impacts of Cannabis Exposure and Withdrawal
2.1. Disruption of the Epigenetic Machinery
There was widespread disruption between the main readers, writers and erasers of the epigenetic code. Hence, there were five hits for the DNA methyltransferases which added the methylation mark to the CpG islands and one hit for TET1 (ten-eleven translocase) which began the process of removing it. There was one hit for telomerase which controlled the end length of the chromosomes, and thus protected them against aging, three hits for polycomb repressors, five hits for the chromatin remodelers (SMARCA’s, SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A) and three hits for the UHRF (Ubiquitin-like with PHD and ring finger domains) family which controlled both DNA methylation and histone methylation and integrated the signaling in the two classes of pathways.
There were 161 hits for the histone methyltransferases with methylate histones and 199 hits for the histone demethylases that remove this mark. There were eleven hits for both the histone acetyltransferases, which acetylate histone tailed and thereby made the genome accessible to the transcription machinery, and eleven hits for the deacetylases which removed this mark.
2.2. Stem Cell Renewal Factors
2.3. Chromosomal Disorders
As noted above, chromosomal disorders hold a prominent place in the patterns of cannabinoid-related carcinogenic and teratogenic disorders. Indeed, when the length of all the chromosomes involved was summed (omitting duplications), it was found that an impressive 1765 megabases of the 3000 megabases of the human genome were directly implicated in the cannabinoid-related genotoxic disorders, which is 58.8% of the human genome. For this reason, the epigenomic findings of the Schrott EWAS dataset were of immense importance.
The proteins which cohere the ends of the human oocyte meiotic spindle so that two (and only two) spindle poles are formed, guiding the formation of two (and only two) daughter cells, are called centrosomal organizers. There were three hits for these proteins, including the nuclear mitotic apparatus protein (NUMA).
The motor proteins which actually move the chromosomes along the microtubules towards minus end of the microtubules and the spindle poles after the anaphase checkpoint is released are called dynein motors which are controlled by a binding partner known as dynactin. There were seven EWAS hits for dynein–dynactin. Interestingly the intracellular kinesin motor moved protein and other cargo in the opposite direction towards the positive end of the microtubule and 218 hits were recorded for kinesin motors.
Thus, these many results clearly impacted and disrupted all the major functions of the chromosomes and likely provided a powerful epigenomic underpinning for the epidemiologically observed carcinogenic and teratogenic pathophysiology. Moreover, the DNA breakage was shown to be a prominent feature of the cannabis exposure of oocytes, sperm, lymphocytes and many other cells, and these finding imply that these lesions were preferentially repaired low-fidelity rather than high-fidelity pathways due to the epigenomic dysregulatory mechanisms.
3. Brain Development and Brain Aging
4. Vascular Aging
The point of these findings was not only to identify that cardiovascular development can be disrupted in these ways but that the induced arterial aging can also induce the system-wide whole organism aging processes through an impairment of the stem cell quiescence/multiplication balance both directly and indirectly.
5. Epigenomic Disruptions by Organ System
The Schrott EWAS contained 73 hits for central nervous system dysfunctions, including the brain, neurological, synaptic, cerebral, neuronal and eye derangements.
At total of 29 hits were noted for cardiovascular disorders, including the heart, atria, ventricles, atrioventricular valves and vessels.
Additionally, 22 hits were noted for orofacial genetic lesions, including the head, sensory organs, palate, nose, anterior eye and ear derangements.
Six hits were identified for limb development directly. Further exploration of a more exhaustive list of the limb morphogens revealed 130 hits for most of the key morphogens involved in limb and digit development, including the fibroblast growth factors (FGFs), retinoid signaling, Wnt signaling, bone morphogenetic pathway signaling and five genes from the sonic hedgehog (shh) pathway, namely MEGF8 (multiple EGF-like domains 8), TMEM107 (transmembrane protein 107), Gli3 (GLI gamily zinc finger 3), CHD7 (chromodomain helicase DNA-binding protein 7) and the patched receptor cofactor. Indeed, 185 hits for the key shh transcription factor Gli3 were found in the Schrott EWAS.
A total of 15 hits were identified for the body wall and embryo.
Additionally, 60 hits were noted for the general otherwise unclassified disorders, including embryonic growth, DNA, mitochondria, microtubules, body trunk, body axis, ovarian reserve, breast disorders, granulocytes, myogenesis, vertebral growth and bone development.
6. Cancer Hits in the Schrott Epigenome-Wide Association Study
The Schrott supplementary file lists 487 hits for “cancer”, 112 hits for “tumor”, 126 hits for “carcinoma”, 36 hits for “neoplasm”, 32 hits for “leukemia” and 17 hits for “lymphoma”. This totals 810 hits for cancer and its synonyms, making this one of the standout and major findings of this EWAS report.
The report specifically mentioned many leukemias, lymphomas, myeloma and tumors of the breast, ovary colorectum, thyroid, liver, brain, pancreas, melanoma, stomach, esophagus and upper aerodigestive tract.
By listing over 30 cancers by name and the genes whose epigenomic modulation was linked with them, these results provided a powerful pan-cancer mechanistic contributory explanation for the patterns of cancer epidemiologically observed in human populations.
7. Aging Implications of the Schrott Epigenome-Wide Association Study Dataset
Two of the key tissues with which researchers were concerned in the present context were the male and female gametes. It was understood that none of the presently available epigenetic clocks were suitable for the application to measure the relatively very hypomethylated ages of the gametes. However it does stand to reason that it may be possible to develop such an algorithmic clock mathematically. What the negative ages might mean, as they may relate to ages prior to birth, has yet to be determined biologically. Hence, it was not possible to measure gametal age directly or epigenomically at the time of writing.
8. Strengths and Limitations
The major limitation of the present work is its preliminary nature in that researchers present an introductory conceptual framework which needs to be filled out and completed by numerous further laboratory studies. The purpose of the present paper is merely to draw attention to this remarkable concordance of cross-disciplinary results and indicate to researchers in the basic sciences that the field is ripe for detailed exploration in many studies with far-ranging consequences.
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