Transcription factors control development by control ling the expression of other genes, some of which are also transcription factors. Groups of transcription fac tors that function together are referred to as transcriptional regulatory modules, and the functional dissection of these modules is an important task of the developmental geneticist and, increasingly, of genome biologists. Some transcription factors activate target genes and others repress them. Still other transcription factors have both activator and repressor functions (so-called bifunctional transcription factors); noncoding RNAs such as microRNAs also interact with target sequences and can activate or repress gene expression. The recruitment of these various activators and repressors within chromatin can be guided by histone modifications such as acetylation, and the regulation of histone modifications is accomplished by histone acetyltransferases and deacetylases. These epigenetic changes to histones are marks that indicate whether a particular gene is likely to be active or inactive. Regulatory mod ules control development by causing different combinations of transcription factors to be expressed at different places and at different times to direct the spatiotemporal regulation of development. By directing differential gene expression across space and time, the binding of various transcriptional regulatory modules to transcriptional complexes is controlled by histone modifications and is a central element of the development of the embryo.

Transcriptional regulatory complexes are localized into clusters of topologically associating domains (TADs) that allow for loop extrusion of DNA between CTCT sites, bringing otherwise distal gene-regulatory elements (i.e., enhancers and silencers) into 3D proximity of target genes to regulate their expression. Such loops regulate the communication between gene-regulatory elements and genes by bringing general transcription factors together with the specific transcription factors that are responsible for creating the selectivity of a transcriptional complex (Fig. 1). Most general transcription factors are found in thousands of these transcriptional complexes throughout the genome, and although each is essential, their roles in development are nonspecific. Specific transcription fac tors bind to enhancers and participate in forming active transcription factor complexes, mostly under the control of epigenetic marks of histone modifications, but only in specific cells or at specific times in development, thereby providing the regulation of gene expression that allows developmental processes to be exquisitely controlled.

Fig1. Activation of transcription occurs in transcriptional complexes that form loops from topologically associated domains (TADs). General transcription factors (blue), and RNA polymerase bind to cis-acting sequences closely adjacent to the messenger RNA (mRNA) transcriptional start site; these cis-acting sequences are collectively referred to as the promoter. More distal enhancer or silencer elements bind specialized and tissue-specific transcription factors. Coactivator proteins facilitate a biochemical interaction between specialized and general transcription factors. (Redrawn from Tjian R: Molecular machines that control genes, Sci Am 272:54–61, 1995.)

The importance of transcription factors in normal development is illustrated by an unusual mutation of HOXD13 that causes synpolydactyly, an incompletely dominant condition in which heterozygotes have interphalangeal webbing and extra digits in their hands and feet. Rare homozygotes have similar but more severe abnormalities and have bone malformations of the hands, wrists, feet, and ankles (Fig. 2). The HOXD13 variant responsible for synpolydactyly is caused by expansion of a polyalanine tract in the amino-terminal domain of the protein; the normal protein contains 15 alanines, whereas the mutant protein contains 22 to 24 alanines. The polyalanine expansion that causes synpolydactyly is likely to act by a gain-of function mechanism, as heterozygosity for a HOXD13 loss-of-function variant has only a mild effect on limb development, characterized by a rudimentary extra digit between the first and second metatarsals and between the fourth and fifth metatarsals of the feet. Regardless of the exact mechanism, this condition demonstrates that a general function for HOX genes is to determine regional identity along specific body axes during development.

Fig2. An unusual gain-of-function variant in HOXD13 creates an abnormal protein with a dominant negative effect. Photographs and radiographs show the synpolydactyly phenotype. (A, B) Hand and radiograph of an individual heterozygous for a HOXD13 variant. Note the branching metacarpal III and the resulting extra digit IIIa. The syndactyly between digits has been partially corrected by surgical separation of III and IIIa-IV. (C, D) Hand and radiograph of an individual homozygous for a HOXD13 variant. Note syndactyly of digits III, IV, and V and their single knuckle; the transformation of metacarpals I, II, III, and V to short carpal-like bones (stars); two additional carpal bones (asterisks); and short second phalanges. The radius, ulna, and proximal carpal bones appear normal. (E, F) Foot and radiograph of the same homozygous individual. Note the relatively normal size of metatarsal I, the small size of metatarsal II, and the replacement of metatarsals III, IV, and V with a single tarsal-like bone (stars). (Reprinted with permission from Muragaki Y, Mundlos S, Upton J, et al: Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13, Science 272:548–551, 1996.)

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اخبار العتبة العباسية المقدسة

شعبة الحرم الشريف تستعد لاستقبال زائري النصف من شهر شعبان

العتبة العباسية المقدسة تنشر لافتات الفرح بمناسبة ذكرى ولادة الإمام المهدي (عجّل الله فرجه)

العتبة العباسية المقدسة تفتتح التسجيل لتأدية الزيارة بالنيابة في ليلة النصف من شعبان

قسم المقام يعلن جاهزيّته لاستقبال زائري النصف من شعبان

المزيد

الآخبار الصحية

الصحة العالمية تكشف حقيقة انتشار فيروس نيباه خارج الهند

متى يصبح محيط الخصر "مؤشر خطر"؟

دراسة تكشف دور "العوامل الوراثية" في تحديد عمر الإنسان

رائحة كريهة في الجسم.. "علامة خفية" أخطر مما تتصور

المزيد

الآخبار التكنلوجية

مايكروسوفت تكشف عن الجيل الثاني من شرائحها للذكاء الاصطناعي

خرافة "ثمانية أكواب يوميا".. كم من الماء يحتاج جسمك فعليا؟

هل توجد حياة خارج كوكبنا؟.. اكتشاف جديد يثير اهتمام العلماء

اكتشاف الخلايا المسؤولة عن فقدان ذاكرة الطفولة

المزيد

مواضيع ذات صلة

Transcriptional Control of Megakaryocytopoiesis: GATA Family Transcription Factors

The Polymerase Chain Reaction Amplifies a Specific DNA Sequence from a Complex Mixture

Role of Developmentally Important Neutrophil-Specific Genes in Disease

Genes Can Be Identified by Their Map Position on the Chromosome

Homologous Recombination Can Repair DNA Damage and Generate Genetic Diversity

During Chain Elongation Each Incoming Aminoacyl-tRNA Moves Through Three Ribosomal Sites

Eukaryotic Translation Initiation Usually Occurs at the First AUG Downstream from the 5′ End of an mRNA

Ribosomes Are Protein-Synthesizing Machines

The Amyloid Precursor Protein Gives Rise to the β-Amyloid Peptide

Nonstandard Base Pairing Often Occurs Between Codons and Anticodons

The Folded Structure of tRNA Promotes Its Decoding Functions

Messenger RNA Carries Information from DNA in a Three-Letter Genetic Code