Človek Genom Project revealed that ~1-2% of our genoma makes functional proteins while the role of the remaining 98-99% remains enigmatic. Researchers have tried to uncover the mysteries surrounding the same and this article throws light on our understanding of its role and implications for human health and diseases.
From the time the Human Genom Project (HGP) was completed in April 20031, it was thought that by knowing the entire sequence of human genome which consists of 3 billion base pairs or ‘pair of letters’, genoma will be an open book using which researchers would be able to pin point exactly how a complex organism as a human being works which will eventually lead to finding our predispositions to various kinds of diseases, enhance our understanding of why disease occurs and finding cure for them as well. However, the situation became very perplexed when the scientists were only able to decipher only a part of it (only ~1-2%) which makes functional proteins that decide our phenotypic existence. The role of 1-2% of the DNA to make functional proteins follows the central dogma of molecular biology which states that DNA is first copied to make RNA, especially mRNA by a process called transcription followed by production of protein by mRNA by translation. In the language of the molecular biologist, this 1-2% of the human genoma codes for functional proteins. The remaining 98-99% is referred to as ‘junk DNA’ or ‘dark pomembno’ which does not produce any of the functional proteins mentioned above and is carried as a ‘baggage’ every time a human being is born. In order to understand the role of the remaining 98-99% of the genoma, ENCODE ( ENCyclopedia Of DNA Elements) project2 was launched in September 2003 by the National Human Genom Research Institute (NHGRI).
The ENCODE project findings have revealed that majority of the dark pomembno’’ comprises of noncoding DNA sequences that function as essential regulatory elements by turning genes on and off in different type of cells and at different points in time. The spatial and temporal actions of these regulatory sequences is still not completely clear, as some of these (regulatory elements) are located very far away from the gene they act upon while in other cases they may be close together.
The composition of some of the regions of human genoma was known even before the launch of the Human Genom Project in that ~8% of the human genoma is derived from viral genomi embedded in our DNA as human endogenous retroviruses (HERVs)3. These HERVs have been implicated in providing innate immunity to humans by acting as regulatory elements for genes that control immune function. The functional significance of the this 8% was corroborated by the findings of the ENCODE project which suggested that majority of the ‘dark pomembno functions as regulatory elements.
In addition to the ENCODE project findings, a vast amount of research data is available from the past two decades suggesting a plausible regulatory and developmental role for the ‘dark pomembno’. Using Genom-wide association studies (GWAS), it has been identified that majority of the noncoding regions of DNA are associated with common diseases and traits4 in razlike v teh regijah delujejo tako, da uravnavajo nastanek in resnost velikega števila kompleksnih bolezni, kot so rak, bolezni srca, možganske motnje, debelost, med mnogimi drugimi5,6. Študije GWAS so tudi pokazale, da se večina teh nekodirajočih zaporedij DNK v genomu prepiše (pretvori v RNA iz DNK, vendar ne prevede) v nekodirajoče RNA in motnje njihove regulacije vodijo do različnih učinkov, ki povzročajo bolezni.7. To kaže na sposobnost nekodirajočih RNA, da igrajo regulativno vlogo pri razvoju bolezni8.
Poleg tega nekatere temne snovi ostanejo kot nekodirajoča DNK in delujejo na regulativni način kot ojačevalci. Kot pove že beseda, ti ojačevalci delujejo tako, da povečajo (povečajo) izražanje določenih beljakovin v celici. To je bilo dokazano v nedavni študiji, kjer zaradi ojačevalnih učinkov nekodirajoče regije DNK bolniki postanejo dovzetni za kompleksne avtoimunske in alergijske bolezni, kot je vnetna črevesna bolezen.9,10, kar vodi do identifikacije novega potencialnega terapevtskega cilja za zdravljenje vnetnih bolezni. Ojačevalci v "temni snovi" so bili vpleteni tudi v razvoj možganov, kjer so študije na miših pokazale, da izbris teh regij vodi do nenormalnosti v razvoju možganov.11,12. Te študije nam lahko pomagajo bolje razumeti kompleksne nevrološke bolezni, kot sta Alzheimerjeva in Parkinsonova bolezen. Pokazalo se je tudi, da ima 'temna snov' vlogo pri razvoju raka v krvi13 kot sta kronična mielocitna levkemija (CML) in kronična limfocitna levkemija (CLL).
Thus, ‘dark matter’ represents an important part of the human genoma than previously realised and has directly influences human health by playing a regulatory role in the development and onset of human diseases as described above.
Ali to pomeni, da se celotna "temna snov" bodisi prepiše v nekodirajoče RNA ali pa ima vlogo ojačevalca nekodirajoče DNK, saj deluje kot regulativni elementi, povezani s predispozicijo, pojavom in variacijami pri različnih boleznih, ki povzročajo ljudi? Do sedaj izvedene študije kažejo močno prevlado enakih in več raziskav v prihodnjih letih nam bo pomagalo natančno začrtati funkcijo celotne 'temne snovi', kar bo vodilo do identifikacije novih tarč v upanju, da bomo našli zdravilo za izčrpavajoče bolezni, ki povzročajo človeško raso.
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Reference:
1. “Human Genome Project Completion: Frequently Asked Questions”. National Human Genom Research Institute (NHGRI). Available online at https://www.genome.gov/human-genome-project/Completion-FAQ Dostop 17. maja 2020.
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8. Martin L, Chang HY. Odkrivanje vloge genomske »temne snovi« pri človeških boleznih. J Clin Invest. 2012;122 (5)1589-1595. https://doi.org/10.1172/JCI60020
9. Inštitut Babraham 2020. Odkrivanje, kako regije 'temne snovi' genoma vplivajo na vnetne bolezni. Objavljeno 13. maja 2020. Dostopno na spletu na https://www.babraham.ac.uk/news/2020/05/uncovering-how-dark-matter-regions-genome-affect-inflammatory-diseases Dostop 14. maja 2020.
10. Nasrallah, R., Imianowski, CJ, Bossini-Castillo, L. et al. 2020. Distalni ojačevalec pri rizičnem lokusu 11q13.5 spodbuja supresijo kolitisa s celicami Treg. Narava (2020). DOI: https://doi.org/10.1038/s41586-020-2296-7
11. Dickel, DE et al. 2018. Za normalen razvoj so potrebni ultra konzervirani ojačevalci. Celica 172, številka 3, P491-499.E15, 25. januar 2018. DOI: https://doi.org/10.1016/j.cell.2017.12.017
12. DNK 'temne snovi' vpliva na razvoj možganov DOI: https://doi.org/10.1038/d41586-018-00920-x
13. Temne snovi so pomembne: razlikovanje subtilnih krvnih rakov z uporabo najtemnejše DNK DOI: https://doi.org/10.1371/journal.pcbi.1007332
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