复旦大学：《医学遗传学 Medical Genetics》课程教学资源（课件讲稿）Chromosome related diseases and Chromosomal disorders Alexander Endler

Chromosome related diseases and chromosomal disorders Alexander endler

Chromosome related diseases and Chromosomal disorders Alexander Endler

Genome The complete human genome consists out of 3 billion base pairs distributed on 23 chromosomes, but only 10%are translated into proteins If unwound and tied together, the strands of dNA would stretch more than 5 feet 150 cm per cell In eukaryotes the dNa is structured in a complex of dna and protein =Chromatin and the basic unit of the chromatin structure is a nucleosome 8968息是 目自 23 4 56 78 101112 131415161718 B88881 19202122 X Y

Genome • The complete human genome consists out of 3 billion base pairs distributed on 23 chromosomes, but only 10% are translated into proteins • If unwound and tied together, the strands of DNA would stretch more than 5 feet = 150 cm per cell . • In eukaryotes the DNA is structured in a complex of DNA and protein =Chromatin and the basic unit of the chromatin structure is a nucleosome

Number of visible bands(depends on resolution Chromosome Ideogram (Giemsa-staining bands) 13.33 13 p 12 121 -11.1 1111 Centromere 11 Long arm, region 1, sub- 12 region 3, sub-region 1 band 2 13.12 13 13.13 13.2 Chromosome number 12 Long arm, region 1, Band 3 133 14.1 14 142 P= short arm, g= long 15 Each arm has numbered regions 21.31 21.2 beginning with 1 nearest the centromere Sub-bands and sub-sub-bands regions) are visible at hi 241 -24.12 resolution and designated by 242 24.21 adding a digit to the number of 243 423 the region Chromosome 12 Chromosome 12

Chromosome Ideogram (Giemsa-staining bands) Centromere Chromosome number = 12 P= short arm, q= long arm. Each arm has numbered regions, beginning with 1 nearest the centromere. Sub-bands and sub-sub-bands ( regions) are visible at higher resolution and designated by adding a digit to the number of the region Number of visible bands(depends on resolution) Long arm, region 1,Band 3 Long arm,region 1, sub￾region 3, sub-region 1, band 2

Nucleosomes consist out of 8 histone proteins wrapped with 2 loops of dNA consisting out of 140 bp each and about 60 bp are linking the nucleosomes together. Histone H1 is bound to the 60 bp linker. The nucleosomes are wound into solenoids that are stabilized by the Histones H1 30 nm DNA HI histone 6-8 nucleosomes 11 nm Nucleosome histone H1 nucleosome Core of 8 Histone molecules linker DNA Nucleosome histone octamer core

Nucleosomes consist out of 8 histone proteins wrapped with 2 loops of DNA consisting out of 140 bp each and about 60 bp are linking the nucleosomes together. Histone H1 is bound to the 60 bp linker .The nucleosomes are wound into solenoids that are stabilized by the Histones H1

shon region of m DNA double helix beads ona-string 11 nm form of chromatin 30-nm chromatin 30 nm fiber of 6688 packed nucleosomes section of chromosome in an extended form 000a 300 nm condensed section of metaphase 700nm entire metaphase 1400nn

Experimental proof that most of the transcribed dna is bound to nucleosomes erythrocyte or oviduct cell Extract chromatin NAsc 1- sitive regions Digest with DNase I Percent maxlmum until 10 of DNA is binding of radioactive c NA Radioactive to DNA extracted DNase CDNA from treated Isolate DNA from chromatin chromatin Red blood cell DNA Globin cdNa Craln cell chromatin Globin CDNA 9400 Fibroblast chromatin+ Globin cDNA 9100 hybridize with probe Probe Red bood cell chromalin Globin cDnA hybridized Red Wood ell chromatin+ Ovalbumin cDNA 90-100 Stme After Weintraub and gnudine, 19?

Experimental proof that most of the transcribed DNA is bound to nucleosomes

The Histone H1 dependant conformation of nucleosomes inhibits the transcription of genes by packing adjacent nucleosomes together into tight arrays that prevent transcription factors and rna polymerases from gaining access to the genes

• The Histone H1 dependant conformation of nucleosomes inhibits the transcription of genes by packing adjacent nucleosomes together into tight arrays that prevent transcription factors and RNA polymerases from gaining access to the genes

Transcription factors Specifity and transcriptional enhancement Transcription factors are proteins that bind to the enhancer or promoter regions and interact such that transcription occurs from only a small group of promoters in any cell. In addition other proteins bind to the tad which have a Histone acety lase activity Histon Acetyl Transferases( HAT) Figure Histone Ac Hyperacetylation Alters Nucleosomal Conformation a nucleosome hypoacetylated histones NAc (blue)is more stable than a nucleosome with acetylated histones (yellow Acetylation renders the histone tails (black more mobile Ac

Transcription factors are proteins that bind to the enhancer or promoter regions and interact such that transcription occurs from only a small group of promoters in any cell. In addition other proteins bind to the TAD which have a Histone Acetylase activity = Histon Acetyl Transferases ( HAT ) Transcription factors Specifity and transcriptional enhancement

There appear to be certain transcriptional activators (such as the glucocorticoid receptor) that can bind to existing nucleosomes and disrupt them Once the nucleosomes are dissociated in the promoter region, other transcription factors can bind Nucleosome DNA is wound around a histone core, forming Initial TF binds TF binding to to a nucleosome part of the histone core Additional factors Histone h1 may bind the Other TFs T complex, further destabilizing the histone core When the histones have been displaced, other TFs mav 1g tao eQ Histone or carrier proteins

There appear to be certain transcriptional activators (such as the glucocorticoid receptor) that can bind to existing nucleosomes and disrupt them. Once the nucleosomes are dissociated in the promoter region, other transcription factors can bind

X Chromosome inactivation Males have Xy females have xX In both gender the amount of X-chromosome encoded gene products are the same There must be a down regulation of X-chromosome encoded genes in females

X Chromosome inactivation Males have XY Females have XX In both gender the amount of X-chromosome encoded gene products are the same There must be a down regulation of X-chromosome encoded genes in females