• Rajiva Raman

Articles written in Resonance – Journal of Science Education

• Dosage Compensation: A Mechanism to Equalize X-linked Gene Products Between the Sexes

The sex chromosomes evolved from a pair of autosomes thatdeviated over a period of time, with one chromosome losingmost of its genes. In many animal groups, females have twoX-chromosomes—a large chromosome with numerous genes.Males have one X and a Y chromosome, which has lost mostgenes except those involved in sex determination and fertility.Thusmales are effectivelymonosomic for the X-chromosome.Monosomy being lethal for other chromosomes, organismsevolved amechanismcalled ‘dosage compensation’ (DC) whichquantitatively equalizes X-linked gene products between thesexes, compensating for their numerical disparity (dosage).Best studied in Drosophila, Caenorhabditis elegans, andmammals,different species adopt different mechanisms of DC. InDrosophila, genes on the male X-chromosome are twice as activeas on each X-chromosome in females. In C. elegans, DCis achieved by the lowered activity of each X-chromosome inXX individuals vis-a-vis the male X. In mammals, the inactivationof an entire X-chromosome in the female results inthe parity between the two sexes. Despite the difference ingross mechanisms, the molecular processes achieving DC areuniform due to chromatin modifications (histone acetylation,methylation, and DNA methylation) and synthesis of variousnoncoding RNAs (lncRNAs ). Together, they regulate the X chromosomeactivity. In mammals, a lncRNA from the inactive X—XIST (X-inactive specific transcript)—binds with thesame X to initiate inactivation. X-chromosome inactivation(XCI) in humans reveals interesting mechanisms for en blocregulation of gene function, as well as modifiers of Mendelian inheritance patterns in genetic disorders.

• Chromatin is a Dynamic Structure

Eukaryotic cells carry a vast amount of DNA packaged in their nucleus as chromatin. During cell division, it further condenses into individual Chromosomes. The basic unit of chromatin is nucleosome which comprises 200 bp of DNA wrapped around an octamer of positively charged histone proteins (2 molecules each H2A, H2B, H3, and H4), and one molecule of Histone H1. The octamer forms a cylinder around which DNA is wrapped ($\sim$146 bp/octamer) and continues to the similar adjacent unit ($\sim$60 bp of linker DNA), forming a string of nucleosomes. The H1 histone brings nucleosomes closer by binding with the linker DNA. These 10--11 nm thick threads further condense into 30 nm fibres, achieving a higher level of compaction by binding with nonhistone chromosomal proteins (e.g., topoisomerase II, condensins and cohesins) to form a scaffold through which the 30 nm fibre passes, forming loops. The average size of the loops is 600 nm, each accommodating approximately 60 kb of DNA. Whereas 85\% of DNA is distributed in the loops, about 15% is associated with the scaffolds. The chromatin which is condensed even at interphase is heterochromatin'. Constitutive heterochromatin comprises tandem repeats of short DNA sequences and is generally devoid of genes, transcription and recombination. A potentially active part of the genome forms the ‘euchromatin’, which also has a differential distribution of DNA that shows up as mutually exclusive G- and R-bands rich in tissue-specific and housekeeping genes, highlighting a highly organised compaction of DNA in the chromatin. Compared to these bands, $>$100 kb long topologically associating domains' (TADs) have been identified at the genome level as the functional unit of chromatin. For its differential functional states, chromatin constantly undergoes condensation and decondensation, mediated by the post-translational modification of histones (e.g. acetylation, methylation of lysine) and the displacement of nucleosomes by an ATP-dependent complex of proteins (e.g. SWI/SNF). DNA methylation is another mode of chromatin modification that affects chromatin function. Thus, a highly dynamic system of chromatin organisation not only encapsulates a large amount of DNA in the nucleus but ensures differential gene function in an orderly fashion.

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