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`Eureka' moments in gene regulation
Books
MOLECULAR MEDICINE TODAY, JUNE 1998
‘Eureka’ moments in gene regulation An enormous amount of human endeavour has been applied to the biological field since the term ‘gene’ was first used to describe the basic unit of heredity. It is now understood that genes are composed of double-helical DNA, and that transduction of genetic signals into cellular function is mediated by the twin processes of transcription and translation – DNA into RNA into protein. In this Landmarks publication, Dr Latchman continues the story to describe the mechanisms by which these processes are regulated. Abundant progress in this area during the past 20 years is presented by means of expert reviews of those publications that have been seminal to understanding eukaryotic gene regulation. Better than a textbook, which merely contains knowledge, this book describes how that knowledge was acquired, and in so doing illustrates the well-worn adage (now axiomatic) that the genesis of all great science lies in asking the right questions. In all, 26 papers have been selected with a knowledgeable bias to illustrate key points in gene regulation, and each of the 13 sections is introduced by a commentary that explains the prismatic nature of each paper and places them in both contemporary and retrospective context. The authorship includes the giants within this field, and it is unsurprising that the combined citation index of these papers exceeds 15 000. Nevertheless, despite this striking collection of luminaries, I confess that I would have been lost without the excellent editorial commentary. The editor has been confronted with a difficult task in selecting a mere handful of papers from 20 years’ research, but then he argues persuasively for each papers’ inclusion, and this broad vision provides fresh perspective to areas that might otherwise be taken for granted. A synopsis of the entire book is provided by the opening argument that different tissues produce different RNA from the same DNA content, and the remainder of the book chronicles the discovery of the mechanisms by which this occurs. There are four broad themes. The first describes how gene regulation is primarily controlled at the transcriptional level – that is, a particular gene is ‘switched on’ in some tissues but not in others – and that post-transcriptional influences (RNA and protein stability) augment this control. The second theme details how transcription factors bind to regulatory DNA sequences within gene pro236
moters to control their expression; additional complexity is provided by the fact the DNA structure (chromatin) controls the access of these transcription factors to their specific targets. The third theme examines some of the ways in which transcription factors are themselves controlled, by phosphorylation or dimerization with auxillary proteins. The book finishes with the wonderful discovery that a single transcription factor can be responsible for the differentiation of a precursor cell into its mature phenotype, when Davis, Weintraub and Lassar identified MyoD in differentiating muscle cells. However, the fascination of this book is not contained within these answers, but rather the manner in which each discovery was made – the ‘eureka’ moment when a simple and elegant solution is found to a question that had vexed researchers of the time. Furthermore, although the book is dominated by molecular biology, the contributions from structural and cellular biology emphasize the importance of an inter-disciplinary approach to understanding gene regulation. Importantly, Dr Latchman has limited his choice to those papers published before 1990, such that these paradigms have now stood the test of time. Two striking examples are the discovery by Weintraub and Groudine that chromatin structure differs in regions where genes are activated, and the elucidation of the zinc-finger DNA-binding protein motif by Miller, McLachlan and Klug. In the former example, experiments that found that the globin gene was sensitive to Dnase I in erythrocytes (active) but not in other tissues (inactive) were extraordinary because they were conducted before the availability of cloned globin gene probes or the development of the powerful Southern blotting method. In the second example, the finding that the transcription factor TFIIIA contained zinc combined with the knowledge that in many metallo-organic compounds zinc is coordinated by cysteine and histidine amino acids, led to an inferred motif structure – the zinc finger – which has been profoundly important to the discovery of many new eukaryotic transcription factors. In his concluding remarks, the editor points the way forward to understanding the mechanisms by which the basic processes of gene regulation described in this book are inter-regulated to produce biological diversity. The authors cited in this book have made it all seem so easy, but the story
continues apace and it can be hoped that todays’ conundrums of gene regulation will again be solved by ingenious methods – and that when the next Landmarks of Gene Regulation is produced, so much more will be understood. Who should read this book? The expert reader will enjoy the fascinating perspective on two decades of scientific endeavour distilled into a logical format. The student should regard Landmarks as a distinction set of lecture notes, with abundant lessons about asking the crucial question. Unfortunately, inspiration of this kind is notoriously impossible to learn. Landmarks in Gene Regulation edited by D.S. Latchman, Portland Press, 1997. £20.00/US $34.00 (xii + 302 pages) ISBN 1 85578 109 3 This is the first volume in the Landmarks in Science and Medicine series. Landmarks in Intracellular Signalling, edited by R.D. Burgoyne and O.H. Peterson, is also available for the same price.
Rory Clifton-Bligh BSc (Med) MBBS Endocrine Fellow Dept of Medicine, Level 5, Addenbrooke’s Hospital, Cambridge, UK CB2 2QQ. Tel: +44 1223 336 853 Fax: +44 1223 336 846 e-mail: [email protected]
Copyright ©1998 Elsevier Science Ltd. All rights reserved. 1357 - 4310/98/$19.00 PII: 51357-4310(98)01281-7
MOLECULAR MEDICINE TODAY, JUNE 1998
‘Eureka’ moments in gene regulation An enormous amount of human endeavour has been applied to the biological field since the term ‘gene’ was first used to describe the basic unit of heredity. It is now understood that genes are composed of double-helical DNA, and that transduction of genetic signals into cellular function is mediated by the twin processes of transcription and translation – DNA into RNA into protein. In this Landmarks publication, Dr Latchman continues the story to describe the mechanisms by which these processes are regulated. Abundant progress in this area during the past 20 years is presented by means of expert reviews of those publications that have been seminal to understanding eukaryotic gene regulation. Better than a textbook, which merely contains knowledge, this book describes how that knowledge was acquired, and in so doing illustrates the well-worn adage (now axiomatic) that the genesis of all great science lies in asking the right questions. In all, 26 papers have been selected with a knowledgeable bias to illustrate key points in gene regulation, and each of the 13 sections is introduced by a commentary that explains the prismatic nature of each paper and places them in both contemporary and retrospective context. The authorship includes the giants within this field, and it is unsurprising that the combined citation index of these papers exceeds 15 000. Nevertheless, despite this striking collection of luminaries, I confess that I would have been lost without the excellent editorial commentary. The editor has been confronted with a difficult task in selecting a mere handful of papers from 20 years’ research, but then he argues persuasively for each papers’ inclusion, and this broad vision provides fresh perspective to areas that might otherwise be taken for granted. A synopsis of the entire book is provided by the opening argument that different tissues produce different RNA from the same DNA content, and the remainder of the book chronicles the discovery of the mechanisms by which this occurs. There are four broad themes. The first describes how gene regulation is primarily controlled at the transcriptional level – that is, a particular gene is ‘switched on’ in some tissues but not in others – and that post-transcriptional influences (RNA and protein stability) augment this control. The second theme details how transcription factors bind to regulatory DNA sequences within gene pro236
moters to control their expression; additional complexity is provided by the fact the DNA structure (chromatin) controls the access of these transcription factors to their specific targets. The third theme examines some of the ways in which transcription factors are themselves controlled, by phosphorylation or dimerization with auxillary proteins. The book finishes with the wonderful discovery that a single transcription factor can be responsible for the differentiation of a precursor cell into its mature phenotype, when Davis, Weintraub and Lassar identified MyoD in differentiating muscle cells. However, the fascination of this book is not contained within these answers, but rather the manner in which each discovery was made – the ‘eureka’ moment when a simple and elegant solution is found to a question that had vexed researchers of the time. Furthermore, although the book is dominated by molecular biology, the contributions from structural and cellular biology emphasize the importance of an inter-disciplinary approach to understanding gene regulation. Importantly, Dr Latchman has limited his choice to those papers published before 1990, such that these paradigms have now stood the test of time. Two striking examples are the discovery by Weintraub and Groudine that chromatin structure differs in regions where genes are activated, and the elucidation of the zinc-finger DNA-binding protein motif by Miller, McLachlan and Klug. In the former example, experiments that found that the globin gene was sensitive to Dnase I in erythrocytes (active) but not in other tissues (inactive) were extraordinary because they were conducted before the availability of cloned globin gene probes or the development of the powerful Southern blotting method. In the second example, the finding that the transcription factor TFIIIA contained zinc combined with the knowledge that in many metallo-organic compounds zinc is coordinated by cysteine and histidine amino acids, led to an inferred motif structure – the zinc finger – which has been profoundly important to the discovery of many new eukaryotic transcription factors. In his concluding remarks, the editor points the way forward to understanding the mechanisms by which the basic processes of gene regulation described in this book are inter-regulated to produce biological diversity. The authors cited in this book have made it all seem so easy, but the story
continues apace and it can be hoped that todays’ conundrums of gene regulation will again be solved by ingenious methods – and that when the next Landmarks of Gene Regulation is produced, so much more will be understood. Who should read this book? The expert reader will enjoy the fascinating perspective on two decades of scientific endeavour distilled into a logical format. The student should regard Landmarks as a distinction set of lecture notes, with abundant lessons about asking the crucial question. Unfortunately, inspiration of this kind is notoriously impossible to learn. Landmarks in Gene Regulation edited by D.S. Latchman, Portland Press, 1997. £20.00/US $34.00 (xii + 302 pages) ISBN 1 85578 109 3 This is the first volume in the Landmarks in Science and Medicine series. Landmarks in Intracellular Signalling, edited by R.D. Burgoyne and O.H. Peterson, is also available for the same price.
Rory Clifton-Bligh BSc (Med) MBBS Endocrine Fellow Dept of Medicine, Level 5, Addenbrooke’s Hospital, Cambridge, UK CB2 2QQ. Tel: +44 1223 336 853 Fax: +44 1223 336 846 e-mail: [email protected]
Copyright ©1998 Elsevier Science Ltd. All rights reserved. 1357 - 4310/98/$19.00 PII: 51357-4310(98)01281-7